Systems and methods for monitoring autonomic health

ABSTRACT

A system for monitoring autonomic health may include an autonomic nerve stimulation (ANS) dose delivery system and a response extractor. The response extractor may be configured to record physiological parameter values including first population data that includes evoked response (ER) values corresponding to evoked physiological responses, and second population data that includes reference values that include no effect (NE) values corresponding to times without a physiological response. The response monitor may calculate evoked response metrics (ERMs) using the first and second population data where each of the ERMs may be dependent on background autonomic activity. The response extractor may analyze the ERMs to provide ERM analysis, and provide an indication of autonomic health using the ERM analysis.

CLAIM OF PRIORITY

This application claims the benefit of priority under 35 U.S.C. § 119(e)of U.S. Provisional Patent Application Ser. No. 62/222,005, filed onSep. 22, 2015, which is herein incorporated by reference in itsentirety.

TECHNICAL FIELD

This application relates generally to medical systems and methods and,more particularly, to systems and methods for monitoring autonomichealth.

BACKGROUND

The automatic nervous system (ANS) regulates “involuntary” organs andmaintains normal internal function and works with the somatic nervoussystem. The ANS includes the sympathetic nervous system and theparasympathetic nervous system. The sympathetic nervous system isaffiliated with stress and the “fight or flight response” toemergencies, and the parasympathetic nervous system is affiliated withrelaxation and the “rest and digest response.”

Autonomic balance reflects the relationship between parasympathetic andsympathetic activity. Autonomic balance may sometimes be referred to asautonomic tone, which refers to a background rate of activity of theANS. Changes in autonomic balance are reflected in changes in heartrate, heart rhythm, contractility, remodeling, inflammation and bloodpressure. Changes in autonomic balance can also be seen in otherphysiological changes, such as changes in abdominal pain, appetite,stamina, emotions, personality, muscle tone, sleep, and allergies, forexample. It is desirable to monitor autonomic health as overall healthdepends on a healthy autonomic balance.

SUMMARY

Various embodiments monitor autonomic health by delivering a dose ofneural stimulation and monitoring subtle, inconsistent physiologicalresponses that have a dependence on background autonomic activity. Theseresponses may be inconsistent as they may only be present for a fractionof the time and further may be a relatively small response. The dose ofneural stimulation may be less than that which would drive anacutely-obvious, physiologic response.

Given the complexity of the ANS and interrelation with manyphysiological functions, these subtle, inconsistent responses are notdetectable simply by observing an acute heart rate or blood pressureresponse. Rather, the subtle, inconsistent responses to the dose ofneural stimulation may be detected using statistical techniques toprovide an evoked response metric (ERM) such as a T-score or Z-score.These subtle, inconsistent physiological responses to the dose of neuralstimulation may have a dependence on the background autonomic activityof the patient, and thus may be used to monitor, by way of example,therapy effectiveness, patient-compliance, or disease progression.Various embodiments may monitor changes in contractility, such as may beused to monitor Cardiac Contractility Modulation (CCM). CCM applied witha regular ON/OFF cycle may be detected if CCM changes contractionintensity or rate either directly or through a neuro mechanism.

An example (e.g. “Example 1”) of a system for monitoring autonomichealth of a person may include an autonomic nerve stimulation (ANS) dosedelivery system and a response extractor. The ANS dose delivery systemmay be configured to provide an ANS dose using stimulation pulses tostimulate autonomic neural tissue at a programmed stimulation dose. TheANS dose delivery system may include a pulse generator configured togenerate stimulation pulses and a controller operably connected to thepulse generator to control the pulse generator to provide the ANS dose.The response extractor is configured to record physiological parametervalues, where the physiologic parameter values include first populationdata that includes evoked response (ER) values corresponding to evokedphysiological responses, and second population data that includesreference values that include no effect (NE) values corresponding totimes without a physiological response. The response monitor maycalculate evoked response metrics (ERMs) using the first and secondpopulation data. Each of the ERMs may be dependent on backgroundautonomic activity. The response extractor may analyze the ERMs toprovide ERM analysis, and provide an indication of autonomic healthusing the ERM analysis.

In Example 2, the subject matter of Example 1 may optionally beconfigured such that the ANS dose delivery system is configured todeliver intermittent ANS that includes a plurality of stimulation burstswherein each stimulation burst includes a plurality of neuralstimulation pulses and successive neural stimulation bursts areseparated by a time without neural stimulation pulses. The responseextractor may be configured to record ER values corresponding to theevoked physiological responses to stimulation bursts and referencevalues that include NE values corresponding to physiological parametervalues that are not evoked physiological responses to stimulationbursts, and Z-score or T-score the recorded physiological parametervalues to obtain a group of ER Z-scores or ER T-scores, wherein the ERMsinclude the group of ER Z-scores or ER T-scores.

In Example 3, the subject matter of any one or any combination ofExamples 1-2 may optionally be configured such that the responseextractor is configured to compare the ERMs to at least one referencevalue to monitor autonomic health.

In Example 4, the subject matter of any one or any combination ofExamples 1-3 may optionally be configured such that the responseextractor is configured to trend the ERMs to monitor autonomic health.

In Example 5, the subject matter of any one or any combination ofExamples 1-4 may optionally be configured such that the ANS dosedelivery system is configured to adjust the ANS dose in steps, and theresponse extractor is configured to calculate an ERM for each step andcompare the ERM to a reference value to monitor autonomic health.

In Example 6, the subject matter of any one or any combination ofExamples 1-5 may optionally be configured such that the ER valuesinclude stimulation effect (SE) values corresponding to direct responsesto stimulation bursts, and the response extractor configured tocalculate ERMs using the SE scores and the second population.

In Example 7, the subject matter of any one or any combination ofExamples 1-6 may optionally be configured such that the system isconfigured to detect a condition, and the response extractor isconfigured to be at least partially disabled in response to the detectedcondition or is configured to be at least partially enabled in responseto the detected condition.

In Example 8, the subject matter of any one or any combination ofExamples 1-7 may optionally be configured such that the system includesa patient status or condition detector. The response extractor may beconfigured to tag the ERMs with the detected patient status orcondition.

In Example 9, the subject matter of any one or any combination ofExamples 1-8 may optionally be configured such that the responseextractor is configured to record stimulation effect (SE) valuescorresponding to direct responses to delivered stimulation pulses orreflex effect (RE) values corresponding to reflex responses afterdelivered stimulation pulses, or both SE values and RE values.

In Example 10, the subject matter of any one or any combination ofExamples 1-9 may optionally be configured such that the ANS dosedelivery system is configured to deliver bursts of neural stimulationpulses, and the response extractor is configured to record NE valuesthat include values during times between successive bursts of neuralstimulation pulses.

In Example 11, the subject matter of any one or any combination ofExamples 1-10 may optionally be configured such that the physiologicalparameter values include at least one of: heart rate values or heartrate variability values.

In Example 1 the subject matter of any one or any combination ofExamples 1-11 may optionally be configured such that the physiologicalparameter values include at least one of: blood pressure values or bloodpressure variability values.

In Example 13, the subject matter of any one or any combination ofExamples 1-12 may optionally be configured such that the physiologicalparameter values include at least one of respiratory values orrespiratory variability values.

In Example 14, the subject matter of any one or any combination ofExamples 1-13 may optionally be configured such that the responseextractor is configured to record electrocardiograms (ECGs), and tocalculate ERMs using a statistical analysis of at least one feature ofthe ECGs to calculate ERMs.

In Example 15, the subject matter of any one or any combination ofExamples 1-14 may optionally be configured such that the ANS dosedelivery system is configured to deliver a vagal nerve stimulation (VNS)dose. The ERMs may include a sympathetic reflex effect (RE) to the VNSdose, and larger ERMs indicate higher background sympathetic activityand lower ERMs indicate lower background sympathetic activity.

An example (e.g. “Example 16”) of a method may include delivering anautonomic neural stimulation (ANS) dose, which may include deliveringstimulation pulses to evoke physiological responses. The method mayfurther include recording physiological parameter values, which mayinclude recording first population data, the first population dataincluding evoked response (ER) values corresponding to the evokedphysiological responses, and recording second population data, thesecond population data including reference values that include no effect(NE) values corresponding to times without an evoked physiologicalresponse. The method may further include calculating evoked responsemetrics (ERMs) using the first and second population data, each of theERMs being dependent on background autonomic activity, analyzing theERMs to provide ERM analysis, and providing an indication of autonomichealth using the ERM analysis. A system may be configured to implementthe method. The system may include hardware, software, firmware, or anycombination thereof to implement the method. In implementing the method,the system may use a set (or sets) of instructions contained on acomputer accessible medium (or media) capable of directing a processoror other controller to perform at least a portion of the method.

In Example 17, the subject matter of Example 16 may optionally beconfigured such that analyzing the ERMs includes comparing the ERMs toat least one reference value to provide the ERM analysis used to providethe indication of autonomic health.

In Example 18, the subject matter of any one or any combination ofExamples 16-17 may optionally be configured such that analyzing the ERMsincludes trending the ERMs to provide the ERM analysis used to providethe indication of autonomic health.

In Example 19, the subject matter of any one or any combination ofExamples 16-18 may optionally be configured such that the ER valuesinclude stimulation effect (SE) values corresponding to direct responsesto delivered stimulation pulses, or reflex effect (RE) valuescorresponding to reflex responses after delivered stimulation pulses, orboth SE values and RE values.

In Example 20, the subject matter of any one or any combination ofExamples 16-19 may optionally be configured such that delivering the ANSdose includes delivering bursts of neural stimulation pulses. The NEvalues may include values during times between successive bursts ofneural stimulation pulses.

In Example 21, the subject matter of any one or any combination ofExamples 16-20 may optionally be configured such that the physiologicalparameter values include at least one of: heart rate values or heartrate variability values.

In Example 22, the subject matter of any one or any combination ofExamples 16-21 may optionally be configured such that the physiologicalparameter values include at least one of: respiratory values orrespiratory variability values.

In Example 23, the subject matter of any one or any combination ofExamples 16-22 may optionally be configured such that the physiologicalparameter values include at least one of: blood pressure values or bloodpressure variability values.

In Example 24, the subject matter of any one or any combination ofExamples 16-23 may optionally be configured such that recordingphysiological parameter values includes recording electrocardiograms(ECGs), and calculating ERMs includes calculating ERMs using astatistical analysis of at least one feature of the ECGs.

In Example 25, the subject matter of any one or any combination ofExamples 16-24 may optionally be configured such that calculating ERMsincludes Z-scoring groups of recorded physiological parameter values toobtain Z-scores for each of the groups, or T-scoring groups of recordedphysiological parameter values to obtain T-scores for each of thegroups.

In Example 26, the subject matter of any one or any combination ofExamples 16-25 may optionally be configured such that delivering the ANSdose includes delivering neural stimulation to a vagus nerve.

In Example 27, the subject matter of any one or any combination ofExamples 16-26 may optionally be configured such that delivering the ANSdose includes delivering neural stimulation to a carotid sinus nerve ora glossopharyngeal nerve.

In Example 28, the subject matter of any one or any combination ofExamples 16-26 may optionally be configured such that delivering the ANSdose includes delivering neural stimulation to a baroreceptor region orto a chemoreceptor region.

An example (e.g. “Example 29”) of a method may include delivering avagal nerve stimulation (VNS) dose and sensing heart rate and recordingheart rate values. The VNS dose may include a plurality of stimulationbursts. Each stimulation burst may include a plurality of neuralstimulation pulses, and successive neural stimulation bursts areseparated by a time without neural stimulation pulses. Sensing heartrate and recording heart rate values may include recording firstpopulation data and second population data. The first population datamay include evoked response (ER) values corresponding to the evokedheart rate effects to stimulation bursts. The second population data mayinclude reference values that include no effect (NE) valuescorresponding to heart rate values that are not evoked heart rateresponses to stimulation bursts. The method may include calculatingevoked response metrics (ERMs) to quantify a relationship between thefirst population data and the second population data. Each of the ERMsmay be dependent on background sympathetic activity. The method mayfurther include analyzing the ERMs to provide ERM analysis, andproviding an indication of autonomic health using the ERM analysis. Asystem may be configured to implement the method. The system may includehardware, software, firmware, or any combination thereof to implementthe method. In implementing the method, the system may use a set (orsets) of instructions contained on a computer accessible medium (ormedia) capable of directing a processor or other controller to performat least a portion of the method.

In Example 30, the subject matter of Example 29 may optionally beconfigured such that the method further includes adjusting the ANS dosein steps, calculating an ERM for each step and comparing the ERM to areference value to monitor autonomic health.

In Example 31, the subject matter of any one or any combination ofExamples 29-30 may optionally be configured such that analyzing the ERMsincludes comparing the ERMs to at least one reference value to providethe ERM analysis used to provide the indication of autonomic health.

In Example 32 the subject matter of any one or any combination ofExamples 29-31 may optionally be configured such that analyzing the ERMsincludes trending the ERMs to provide the ERM analysis used to providethe indication of autonomic health.

In Example 33, the subject matter of any one or any combination ofExamples 29-32 may optionally be configured such that the method furtherincludes detecting a patient status or a patient condition, and taggingthe ERMs with the detected patient status or condition.

In Example 34, the subject matter of any one or any combination ofExamples 29-33 may optionally be configured such that the ER values inthe first population data includes stimulation effect (SE) valuescorresponding to direct responses to stimulation bursts, and calculatingERMs includes analyzing for a SE signature.

In Example 35, the subject matter of any one or any combination ofExamples 29-34 may optionally be configured such that the ER values inthe first population data include reflex effect (RE) valuescorresponding to reflex responses after stimulation bursts, andcalculating the ERM to quantify the relationship between the firstpopulation data and the second population data includes analyzing for aRE signature.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates increasing VNS intensity from the left side to theright side of the figure, and further illustrates intensity thresholdsthat elicit various physiological responses to VNS.

FIG. 2 illustrates increasing VNS intensity from the left side to theright side of the figure and a subtle, inconsistent physiologic response(e.g. a subtle, inconsistent change in heart rate, blood pressure and/orrespiration) for the VNS, and further illustrates an intensity thresholdthat elicits an acutely-observable and significant (e.g. 5% reduction ormore) reduced heart rate response to VNS.

FIG. 3 illustrates increasing VNS intensity from the left side to theright side of the figure and a subtle and/or inconsistent physiologicresponse (e.g. a subtle change in heart rate, blood pressure and/orrespiration) for the VNS, and further illustrates an intensity thresholdthat elicits an acutely-observable physiological response such as anacutely-observable and significant reduced heart rate response to VNSand another intensity threshold that elicits another physiologicalresponse (e.g. laryngeal vibration) to VNS.

FIG. 4 illustrates a train of neural stimulation bursts (e.g.parasympathetic stimulation bursts). The train of neural stimulationbursts may be referred to as intermittent neural stimulation (INS).

FIG. 5A illustrates an efferent parasympathetic target, and FIG. 5Billustrates a direct response on circulation (e.g. lowered heart rate orblood pressure) to the parasympathetic stimulation pulse train, asillustrated in FIG. 4, at an efferent parasympathetic target, asillustrated in FIG. 5A.

FIGS. 6A and 6B illustrate efferent and afferent parasympatheticstimulation with an afferent parasympathetic pathway carrying signals tothe CNS and an efferent sympathetic pathway from the CNS carrying reflexstimulation to the target. FIG. 6B illustrates a direct and reflexresponse of the circulation (e.g., heart rate decrease then increase orblood pressure decrease then increase) to the parasympatheticstimulation pulse train, as illustrated in FIG. 4, at an efferentparasympathetic target as illustrated in FIG. 6A.

FIGS. 7A-7B illustrate various embodiments for monitoring a response toan intermittent NS burst.

FIGS. 8A-8B provides simple illustrations of how the backgroundautonomic activity may cause changes in an evoked response.

FIG. 9 illustrates, by way of example and not limitation, an embodimentof a response extractor configured for use to analyze an evoked responseto detect subtle, inconsistent changes in the evoked response.

FIG. 10 illustrates an example of a system that includes an autonomichealth monitor.

FIG. 11 illustrates an example of a system that includes an implantablemedical system and an autonomic health monitor.

FIG. 12 illustrates an example of an implantable medical system thatincludes an electrical therapy delivery system and an autonomic healthmonitor.

FIG. 13 illustrates an example of an implantable medical system, similarto the system illustrated in FIG. 12 that includes a cardiac rhythmmanagement system and the autonomic health monitor.

FIG. 14 illustrates an example of an implantable medical system similarto the system illustrated in FIG. 12 that includes a neurostimulationsystem and the autonomic health monitor.

FIG. 15 illustrates an example of an implantable medical system thatincludes a neurostimulation system and the autonomic health monitor thatshare an ANS dose delivery system.

FIG. 16 illustrates an example of a system that includes an autonomichealth monitor that uses a response extractor configured to compareresponses to trend responses.

FIG. 17 illustrates an example of a method performed by the responseextractor in FIG. 16.

FIG. 18 illustrates an example of a system that includes an autonomichealth monitor that includes an ANS dose delivery system with a doseadjustment routine, and that includes a response extractor to identify aresponse threshold.

FIG. 19 illustrates an example of a method performed by the responseextractor in FIG. 18.

FIGS. 20A-20C illustrate some Venn diagrams for the first populationdata and the second population data.

FIG. 21 illustrates an example of first population data and the secondpopulation data that may be extracted from a sensed physiological signalduring intermittent neural stimulation.

FIG. 22 illustrates, by way of example and not limitation, an embodimentof a response extractor with optional features to enable or disable theresponse extractions and optional features to correlate an extractedresponse to a patient status or condition.

FIG. 23 illustrates, by way of example, a method for titrating VST usinga subtle physiologic response.

FIG. 24 illustrates, by way of example, a method for monitoringautonomic health using a subtle physiological response to an ANS dosedetected using a calculated score.

FIG. 25 illustrates, by way of example, a method for monitoringautonomic health using a subtle physiological response to an ANS dosedetected using an evoked response metric.

FIGS. 26A and 26B illustrate, by way of example, a heat map (z(t,j,0.01)) of Z-scores for a plurality of trials over a number days thatprovides a visual illustration of a signature for a stimulation effect(SE) and rebound effect (RE), and further illustrates Z-scores atdifferent points along the physiological waveform during the trial.

FIGS. 27A-27C illustrate additional examples for quantifying acomparison between the SE and the reference values.

FIG. 28 illustrates, by way of example, ANS dose timing to provideanother way in which the first and second population data may becaptured.

FIG. 29 illustrates, by way of example, an embodiment of a system thatincludes an ANS dose delivery system, a dose response monitor, and anexternal device.

FIG. 30 illustrates a system embodiment configured to extract an evokedresponse and control stimulation using the extracted response.

FIG. 31 illustrates a VNS system, according to various embodiments.

FIG. 32 illustrates an implantable medical device (IMD) having a neuralstimulation (NS) component and a cardiac rhythm management (CRM)component according to various embodiments of the present subjectmatter.

FIG. 33 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments.

FIG. 34 illustrates a system including an implantable medical device(IMD) and an external system or device, according to various embodimentsof the present subject matter.

FIG. 35 illustrates a system including an external device, animplantable neural stimulator (NS) device which may be used to provide aNS dose or therapy and an implantable cardiac rhythm management (CRM)device, according to various embodiments of the present subject matter.

FIG. 36 illustrates a system embodiment in which an IMD is placedsubcutaneously or submuscularly in a patient's chest with lead(s) 3607positioned to stimulate a vagus nerve.

FIG. 37 illustrates a system embodiment that includes an implantablemedical device (IMD) with satellite electrode(s) positioned to stimulateat least one neural target.

FIG. 38 illustrates an IMD placed subcutaneously or submuscularly in apatient's chest with lead(s) positioned to provide a CRM therapy to aheart, and with lead(s) positioned to stimulate and/or inhibit neuraltraffic at a neural target, such as a vagus nerve, according to variousembodiments.

FIG. 39 illustrates an IMD with lead(s) positioned to provide a CRMtherapy to a heart, and with satellite transducers positioned tostimulate/inhibit a neural target such as a vagus nerve, according tovarious embodiments.

FIG. 40 illustrates, by way of example, an IMD with a lead positioned tostimulate and/or inhibit neural traffic at a vagus nerve, according tovarious embodiments.

FIG. 41 is a block diagram illustrating an embodiment of an externalsystem.

FIG. 42 illustrates, by way of example and not limitation, an embodimentof a system, various components of which may be used to store thepopulation data and process the population data to score the data.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

The ANS regulates “involuntary” organs, while the contraction ofvoluntary (skeletal) muscles is controlled by somatic motor nerves.Examples of involuntary organs include respiratory and digestive organs,and also include blood vessels and the heart. Often, the ANS functionsin an involuntary, reflexive manner to regulate glands, to regulatemuscles in the skin, eye, stomach, intestines and bladder, and toregulate cardiac muscle and the muscle around blood vessels, forexample.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.Afferent nerves convey impulses toward a nerve center, and efferentnerves convey impulses away from a nerve center.

Stimulating or inhibiting the sympathetic or parasympathetic nervoussystems can cause heart rate, blood pressure and other physiologicalresponses. For example, stimulating the sympathetic nervous systemdilates the pupil, reduces saliva and mucus production, relaxes thebronchial muscle, reduces the successive waves of involuntarycontraction (peristalsis) of the stomach and the motility of thestomach, increases the conversion of glycogen to glucose by the liver,decreases urine secretion by the kidneys, and relaxes the wall andcloses the sphincter of the bladder. Stimulating the parasympatheticnervous system (inhibiting the sympathetic nervous system) constrictsthe pupil, increases saliva and mucus production, contracts thebronchial muscle, increases secretions and motility in the stomach andlarge intestine, and increases digestion in the small intention,increases urine secretion, and contracts the wall and relaxes thesphincter of the bladder. The functions associated with the sympatheticand parasympathetic nervous systems are many and can be complexlyintegrated with each other.

A reduction in parasympathetic nerve activity contributes to thedevelopment and progression of a variety of cardiovascular diseases.Examples of such diseases or conditions include HF, hypertension, andcardiac remodeling. These conditions are briefly described below.Autonomic neurostimulation may be used to stimulate or inhibit autonomicneural targets in the patient. By way of example and not limitation,autonomic neural targets may include the vagus nerve including variouslocations along the vagus nerve such as the cervical region and cardiacnerves, the carotid sinus nerve, the glossopharyngeal nerve,baroreceptors, chemoreceptors, fat pads spinal cord, and nerve roots.Medicines, such as beta blockers, may be used to adjust autonomicbalance.

HF refers to a clinical syndrome in which cardiac function causes abelow normal cardiac output that can fall below a level adequate to meetthe metabolic demand of peripheral tissues. HF may present itself ascongestive heart failure (CHF) due to the accompanying venous andpulmonary congestion. HF can be due to a variety of etiologies such asischemic heart disease. HF patients have reduced autonomic balance,which is associated with LV dysfunction and increased mortality.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to HF. Hypertension generally relates tohigh blood pressure, such as a transitory or sustained elevation ofsystemic arterial blood pressure to a level that is likely to inducecardiovascular damage or other adverse consequences. Hypertension hasbeen defined as a systolic blood pressure above 140 mm Hg or a diastolicblood pressure above 90 mm Hg. Consequences of uncontrolled hypertensioninclude, but are not limited to, retinal vascular disease and stroke,left ventricular hypertrophy and failure, myocardial infarction,dissecting aneurysm, and renovascular disease. A large segment of thegeneral population, as well as a large segment of patients implantedwith pacemakers or defibrillators, suffer from hypertension. The longterm mortality as well as the quality of life can be improved for thispopulation if blood pressure and hypertension can be reduced.

Cardiac remodeling refers to a complex remodeling process of theventricles that involves structural, biochemical, neurohormonal, andelectrophysiologic factors, which can result following a myocardialinfarction (MI) or other cause of decreased cardiac output. Ventricularremodeling is triggered by a physiological compensatory mechanism thatacts to increase cardiac output due to so-called backward failure whichincreases the diastolic filling pressure of the ventricles and therebyincreases the so-called preload (i.e., the degree to which theventricles are stretched by the volume of blood in the ventricles at theend of diastole). An increase in preload causes an increase in strokevolume during systole, a phenomena known as the Frank-Starlingprinciple. When the ventricles are stretched due to the increasedpreload over a period of time, however, the ventricles become dilated.The enlargement of the ventricular volume causes increased ventricularwall stress at a given systolic pressure. Along with the increasedpressure-volume work done by the ventricle, this acts as a stimulus forhypertrophy of the ventricular myocardium. The disadvantage ofdilatation is the extra workload imposed on normal, residual myocardiumand the increase in wall tension (Laplace's Law) which represent thestimulus for hypertrophy. If hypertrophy is not adequate to matchincreased tension, a vicious cycle ensues which causes further andprogressive dilatation. As the heart begins to dilate, afferentbaroreceptor and cardiopulmonary receptor signals are sent to thevasomotor central nervous system control center, which responds withhormonal secretion and sympathetic discharge. The combination ofhemodynamic, sympathetic nervous system and hormonal alterations (suchas presence or absence of angiotensin converting enzyme (ACE) activity)account for the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction. It hasbeen shown that the extent of ventricular remodeling is positivelycorrelated with increased mortality in post-MI and heart failurepatients.

By way of example, vagal stimulation therapy (VST) has been proposed totreat various cardiovascular diseases, including HF. VST is beinginvestigated a potential therapy for heart failure amelioration.Efferent and afferent vagus nerve fibers modulate heart rate throughdirect innervation of the SA node and centrally though a modulation ofthe sympathetic and parasympathetic balance. Acute VST can decreaseheart rate and chronic VNS can blunt heart failure progression inpre-clinical models. Early VNS studies intentionally decreased heartrate and found a reduction in post MI mortality. However, VST-inducedbradycardia could cause symptomatic side effects for HF patients,especially during exercise, and could provide undesired inotropic anddromotropic effects. It is believed that beneficial effects of VST oncardiac function and remodeling are not necessarily mediated viasignificant heart rate reduction that is acutely observable. That is,VST can benefit HF patients without the undesired chronotropic effectsassociated with VST as well as other side effects due to high intensitystimulation such as coughing, etc. Rather, anti-inflammatory,anti-sympathetic, and anti-apoptosis mediators are triggered at lowerVST intensities than intensities at which a heart rate reduction isrealized. These mediators function as pathways through which the VSTprovides the therapeutic effects for cardiovascular disease. Vagal nervesignaling plays an important role in modulating systemic inflammatoryresponse and apoptosis, which are important in the development andprogression of HF. Low level of efferent vagal nerve stimulation (1 Hz)has been shown to attenuate the release of proinflammatory cytokines(such as tumor necrosis factor, interleukin, etc.) from macrophagethrough nicotinic acetylcholine receptors (see Borovikova, LV. Nature.2000, 405: 458-462). Our internal preclinical data suggests that thetherapeutic level of VST could modulate inflammatory and apoptosissignaling pathways without lowering heart rate, where the preclinicalstudies used a neural stimulator prototype to deliver VST thatnon-selectively stimulates both afferent axons and efferent axons in thevagus nerve according to a predetermined schedule for the VST (e.g.Hamann et al., Vagus nerve stimulation improves left ventricularfunction in a canine model of chronic heart failure, Eur Journal HeartFail 2013; 15:1319-1326). ANS may be delivered non-selectively toafferent and efferent axons at low levels to avoid or inhibitbradycardia responses induced by stimulation of the vagus nerve. ANS maybe delivered with a low ANS intensity that is therapeutically effectivefor the cardiovascular disease and that does not significantly drive alower intrinsic heart rate. Heart rate may be maintained during ANSwithout resort to bradycardia support pacing of the myocardium duringANS. ANS may be delivered with a therapeutically-effective dose toachieve its beneficial effects on autonomic function without significantchronotropic side effects from acutely-observable and significant heartrate drops (e.g. 5% mean heart rate drop or more), improving thetolerability. For example, an ANS dose (e.g. a dose of vagalstimulation) may have a, intensity that causes a subtle, inconsistentresponse that is detectable using statistical measures such as a T-scoreor Z-score, as discussed in more detail below.

Furthermore, it has been observed that the evoked response to low levelvagal stimulation is dependent on the background sympathetic activity ofthe patient. As will be discussed in more detail below, variousembodiments may use low level ANS doses induce evoked responses that maybe used as a surrogate for monitoring the background autonomic activity.Thus, a brief discussion of low-level ANS is provided below using vagalnerve stimulation (VNS) as an example. Given the complexity of the ANSand interrelation with many physiological functions, these subtle,inconsistent responses are not detectable simply by observing an acuteheart rate or blood pressure response. Rather, the subtle, inconsistentresponses to the dose of neural stimulation may be detected usingstatistical techniques to provide an evoked response metric (ERM) suchas a T-score or Z-score. These subtle, inconsistent physiologicalresponses to the dose of neural stimulation may have a dependence on thebackground autonomic activity of the patient, and thus may be used tomonitor, by way of example, therapy effectiveness, patient-compliance,disease progression and cardiac contractility modulation.

The vagus nerve is a complex physiological structure with many neuralpathways that are recruited at different stimulation thresholds. Variousphysiological responses to VNS are associated with various VNS doses.For example, FIG. 1 illustrates increasing VNS intensity from the leftside to the right side of the figure, and further illustrates intensitythresholds that elicit various physiological responses to VNS. VNScauses a physiological response “A” at a lower intensity than anintensity at which VNS causes a physiological response “B”, which occursat a lower VNS intensity than an intensity at which VNS causes aphysiological response “C”. Stated another way, VNS has to reach acertain level before triggering response “A,” and has to reach higherlevels to trigger responses “B” and “C”.

The physiological responses at the lower VNS intensities may havetherapeutically-effective results for cardiovascular diseases such asHF. These intensities may be used to deliver a therapy (VST). Theseresponses mediate or provide pathways for these therapies. Examples ofsuch responses that are beneficial for HF at the lower VNS intensitiesinclude anti-inflammation, anti-sympathetic, and anti-apoptosisresponses, and an increased NO. The physiological responses at thehigher VNS intensities may not be desirable. Examples of responses tohigher VNS intensities that may reduce the ability of the patient totolerate VNS include, but are not limited to, reduced heart rate,prolonged AV conduction, vasodilation, and coughing. Not only may thephysiological responses at the lower VNS intensities be therapeutic, theresponses are dependent on the background autonomic activity and may beused as a surrogate for the autonomic health of the patient.

The intensity of the VNS can be adjusted by adjusting parameter(s) ofthe stimulation signal. Generally, dose may be changed by changing theamount of charge delivered over a period of time. For example, theamplitude of the signal (e.g. current or voltage) can be increased toincrease the intensity of the signal. Other stimulation parameter(s) canbe adjusted as an alternative to or in addition to amplitude. Forexample, stimulation intensity can vary with the frequency of thestimulation signal, a stimulation burst frequency, a pulse width, apulse duty cycle and/or a burst duty cycle.

FIG. 2 illustrates increasing VNS intensity from the left side to theright side of the figure and a subtle, inconsistent physiologic response(e.g. a subtle, inconsistent change in heart rate, blood pressure and/orrespiration) for the VNS, and further illustrates an intensity thresholdthat elicits an acutely-observable and significant (e.g. 5% reduction ormore) reduced heart rate response to VNS. The subtle, inconsistentresponse may occur over a range in which the response is present in asmaller percentage of time (e.g. less consistent) toward the left sideof the figure and the response is present in a larger percentage of time(e.g. more consistent) toward the right side of the figure. Similarly,the responses may be smaller toward the left side of the figure andlarge toward the rights side of the figure. Larger periods of time maybe used to detect the subtle, inconsistent responses toward the leftside of the figure and shorter periods of time may be used to detect thelarger and/or more consistent responses toward the right side of thefigure. Techniques described herein may be used to detect the subtleand/or inconsistent physiological response and/or detect non-subtleeffects that are intermittent and not seen with acute testing. Asdescribed herein, these techniques may be used to monitor autonomichealth by delivering a VNS dose and detecting the subtle and/orinconsistent physiological responses caused by the dose, which providean indication of the background autonomic activity.

Some embodiments may include a system for delivery a therapy (e.g. VST).For an open loop VST system, physiologic parameter(s) may be monitoredduring VST testing. This VST testing may be based on a relatively largehuman population to determine the heart rate threshold. The VST testingmay also be performed specifically for a patient during the implantationprocedure using a process that verifies capture of the vagus nerve usingobserved heart rate reduction, that determines the intensity thresholdat which the heart rate reduction is observed, and that uses theintensity threshold to provide and set the VST intensity below the heartrate threshold that causes the acutely observable and obvious heart ratereduction. The subtle, inconsistent response found at lower intensitiesmay have a heart rate effect, but the heart rate effect is a subtleeffect that is not an acutely-observable and significant drop in heartrate. For example, vagal stimulation pulses of a first amplitude maycapture some nerve fibers in the cervical vagus nerve to cause thesubtle heart rate effect, and vagal stimulation pulses of a second,higher, amplitude may capture addition nerve fibers in the cervicalvagus nerve to cause the acutely-observable and significant drop inheart rate. It is believed that effective cardiovascular therapy, suchas heart failure (HF) therapy, may be titrated to provide a targetedsubtle, inconsistent physiologic response.

FIG. 3 illustrates increasing VNS intensity from the left side to theright side of the figure and a subtle and/or inconsistent physiologicresponse (e.g. a subtle change in heart rate, blood pressure and/orrespiration) for the VNS, and further illustrates an intensity thresholdthat elicits an acutely-observable physiological response such as anacutely-observable and significant reduced heart rate response to VNSand another intensity threshold that elicits another physiologicalresponse (e.g. laryngeal vibration) to VNS. Preclinical studies indicatethat laryngeal vibration is detected at a lower VNS intensity thresholdthan the VNS intensity threshold for eliciting the acutely observableheart rate response. In some embodiments, the intensity threshold thatcauses the acutely-observable and significant reduced heart rateresponse may function as an upper boundary for allowable adjustments tothe intensity to find the sweet spot, or may be used with a positive ornegative offset to identify upper boundary for allowable adjustments. Insome embodiments, the intensity threshold that causes the laryngealvibrations may function as lower boundary for allowable adjustments tothe intensity to find the sweet spot, or may be used with a positive ornegative offset to identify lower boundary for allowable adjustments.FIG. 3 illustrates, by way of example, a candidate dose range that mayextend through a range of intensities.

In embodiments in which VNS is delivered for a therapy, the therapeuticefficacy of the VST can be assessed acutely (e.g. within seconds orminutes) such as may be beneficial for a closed loop system or during animplantation procedure, and can be assessed on a longer term basis (e.g.on the order of hours, days, weeks, and months) such as may bebeneficial to provide follow-programming updates for either open loop orclosed loop systems. Examples of acute markers which could be measuredto tell if the dose is in the therapeutic effective range includeanti-inflammatory cytokines and autonomic balance markers. Examples ofanti-inflammatory cytokines include serum TNF-alpha, IL-1, IL6, etc.Examples of autonomic balance markers include plasma NE (an indicator ofsympathetic tone), heart rate variability (HRV) and heart rateturbulence (HRT). Longer term assessment of therapeutic efficacy can bedetermined using various methods currently used to monitor theprogression of heart failure (e.g. electrogram readings and variousmeasures of cardiac output, contractility, and size of the leftventricle). Other physiological responses that in and of themselves arenot beneficial for the therapy, such as laryngeal vibration, may be usedif their response threshold has a known relationship to trigger desiredmediators (e.g. mediators, anti-apoptosis mediator, andanti-sympathetic) through which the applied VST provides effectivetherapy for the cardiovascular disease.

Various embodiments of the present subject matter may monitor an evokedresponse of neural stimulation for a desirable subtle and/orinconsistent response that may be detected using statistical analysis(e.g. T-score or Z-score). This subtle and/or inconsistent response maybe used to monitor autonomic health. This subtle and/or inconsistentresponse may be used to monitor autonomic health may be used to controlor evaluate a therapy. An evoked response may be illustrated usingintermittent neural stimulation as discussed below.

FIG. 4 illustrates a train of neural stimulation bursts (e.g.parasympathetic stimulation bursts). The train of neural stimulationbursts may be referred to as intermittent neural stimulation (INS). Thetime-course of neural stimulation may alternate between intervals ofstimulation being ON when pulse(s) are delivered and stimulation beingOFF when no pulses are delivered. Each burst includes a plurality ofpulses (not illustrated) within the burst. The duration of thestimulation ON interval is sometimes referred to as the stimulationduration or burst duration. The start of a stimulation ON interval is atemporal reference point NS Event. The time interval between successiveNS Events is the INS Interval, which is sometimes referred to as thestimulation period or burst period. For an application of neuralstimulation to be intermittent, the stimulation duration (i.e., ONinterval) must be less than the stimulation period (i.e., INS Interval)when the neural stimulation is being applied. The duration of the OFFintervals of INS are controlled by the durations of the ON interval andthe INS Interval. The duration of the ON interval relative to the INSInterval (e.g., expressed as a ratio) is sometimes referred to as theduty cycle of the INS. In the illustration, each burst has an equalduration (e.g. on the order of 10 seconds) and the bursts are separatedby a burst period (e.g. on the order of one minute). The duration and/orburst period may be adjusted during the therapy to adjust the therapydose and the evoked response. The dose and evoked response may beadjusted by changing the amplitude, pulse frequency, and/or pulse widthof the neural stimulation pulses within the burst.

FIGS. 5A, 5B, 6A and 6B illustrate applications of the neuralstimulation illustrated in FIG. 4 to a target to elicit an ANS effect onheart rate (HR) or blood pressure (BP). It is noted that the ANS alsohas an effect on respiration. Negative-going waveforms illustrated inFIGS. 5B and 6B indicate a decrease in HR or BP, such as expected fromparasympathetic stimulation, while positive-going waveforms indicate anincrease in HR or BP, such as expected from sympathetic stimulation.FIGS. 5A and 5B illustrate stimulation parameters adjusted to elicit adirect parasympathetic effect. FIGS. 6A and 6B illustrate stimulationparameters adjusted to elicit direct parasympathetic and reflexsympathetic effects.

FIG. 5A illustrates an efferent parasympathetic target, and FIG. 5Billustrates a direct response on circulation (e.g. lowered heart rate orblood pressure) to the parasympathetic stimulation pulse train, asillustrated in FIG. 4, at an efferent parasympathetic target, asillustrated in FIG. 5A. Action potentials in afferent nerves traveltoward the central nervous system (CNS), and action potentials inefferent nerves travel away from the CNS. As illustrated in FIG. 5B, thedirect response referred to herein as a stimulation effect (SE)attributed to the selective stimulation of the efferent pathway followsthe time course of neural stimulation pulses and returns to baselinebetween stimulation bursts. The efferent stimulation in this exampleresults in a small direct response in HR or BP that does not elicit ameasurable reflex response, as indicated by immediate return to baselineof the response following termination of the stimulation burst.

FIGS. 6A and 6B illustrate efferent and afferent parasympatheticstimulation with an afferent parasympathetic pathway carrying signals tothe CNS and an efferent sympathetic pathway from the CNS carrying reflexstimulation to the target. FIG. 6B illustrates a direct and reflexresponse of the circulation (e.g., heart rate decrease then increase orblood pressure decrease then increase) to the parasympatheticstimulation pulse train, as illustrated in FIG. 4, at an efferentparasympathetic target as illustrated in FIG. 6A. As illustrated in FIG.6B, the stimulation of the efferent pathway provides a direct responsereferred to herein as a stimulation effect (SE) and a reflex responsereferred to herein as a reflex effect (RE). In this example, theefferent stimulation elicits a reflex effect when baroreceptors in FIG.6A respond to the lowered HR or BP, sending impulses to the CNS in theafferent nerve illustrated in FIG. 6A and thereby eliciting acompensatory sympathetic reflex, which may also be referred to as anantagonistic sympathetic reflex, that increases HR and BP via impulsesconveyed from the CNS in the sympathetic efferent pathway illustrated inFIG. 6A. As illustrated in FIG. 6B, the stimulation effect ends quicklyafter the end of the stimulation burst, whereas the reflex effectcontinues measurably after the end of the stimulation burst. It is notedthat the reflex response is a complex reaction that may have othercontributing factors such as chemoreceptor activity. Furthermore, thestimulation may be a non-selective, bidirectional stimulation thatelicits action potentials in the parasympathetic nerve both in theafferent direction toward the CNS as well as in the efferent direction.The elicited action potentials in the afferent direction toward the CNSalso affect the evoked response. The present subject matter is notlimited to a particular mechanism.

FIGS. 7A-7B illustrate various embodiments for monitoring a response toan intermittent NS burst. Multiple bursts can be analyzed, according tovarious embodiments. Each figure illustrates one neural stimulationburst among a plurality of INS stimulation bursts of a programmed NStherapy. The NS burst includes a plurality of NS pulses that arepreceded and followed by a time without NS pulses. In one embodimentillustrated in FIG. 7A, an ANS signal may be monitored over time andmarked with the NS event, which is a time point with a fixed offset fromthe start of the NS burst. The NS event offset from the NS burst startmay be a zero offset, a negative offset, or a positive offset dependingon various signal analysis embodiments. The NS event may divide the ANSsignal into a Pre-Event Signal and a Post-Event Signal. As illustratedin FIG. 7B, the pre-event signal may contain a pre-event baseline andthe post-event signal may contain an evoked response and a post-eventbaseline. The evoked response may include a direct response (stimulationeffect (SE)) and a reflex response (reflex effect (RE)).

As identified previously, the subtle and/or inconsistent response may beused to monitor autonomic health. The autonomic nervous systeminfluences, among other things, the performance of the heart. Theaccelerative effects of the sympathetic nervous system on heart rate aredependent on the background level of vagal activity. For example,sympathetic heart rate effects are substantially smaller with highlevels of vagal tone than with low vagal background activity, and vagaleffects are progressively stronger with increasing sympatheticbackground activity. Each of the two autonomic divisions can bothinhibit and enhance the activity of the other via effects on the releaseof neurotransmitters at the synaptic junctions. The inhibition of thecardiac effects from sympathetic nerve stimulation by the presence ofbackground vagus nerve stimulation has been described using the term“accentuated antagonism.”

Embodiments of the present subject matter may monitor an evoked responseto an ANS dose to monitor background autonomic activity. The reflexeffect (RE) of an evoked response to an ANS dose is opposite to thestimulation effect (SE) to the ANS dose. For example, an elevatedsympathetic activity in the background will be more sensitive to asympathetic response effect to parasympathetic stimulation. Moresympathetic neurotransmitters at the synaptic junctions may make thesympathetic response effect more detectable by being more consistentlypresent and/or by being a greater response when present.

FIGS. 8A-8B provides simple illustrations of how the backgroundautonomic activity may cause changes in an evoked response. The figuresimply illustrates a function between the background activity and evokedresponse as a linear function to illustrate that larger backgroundactivity corresponds to larger evoked responses. This function may notbe linear. However, these figures illustrate the general concept thatmore sympathetic neurotransmitters at the synaptic junctions may makethe sympathetic response effect more detectable by being moreconsistently present and/or by being a greater response when present,and more parasympathetic neurotransmitters at the synaptic junctions maymake parasympathetic response effect more detectable by being moreconsistently present and/or by being a greater response when present.

For example, FIG. 8A provides a simple illustration of a sympatheticevoked response for a given parasympathetic dose, where the evokedresponse varies based on sympathetic background activity according to afunction which is simply illustrated as a linear function. Similarly,FIG. 8B provides a simple illustration of a parasympathetic evokedresponse for a given sympathetic dose, where the evoked response variesbased on parasympathetic background activity according to a functionwhich is simply illustrated as a linear function. The dose affects theSE. In each of these illustrations, a change in the reflex effect (RE)for a given dose may indicate a change (Δ) in the background activity.Where the background activity has the same tone (e.g. parasympathetic orsympathetic) as the RE as illustrated in both FIGS. 8A and 8B, then anobserved increase in the RE corresponds to an increase in the backgroundtone. Where the background activity and the RE have different tone, thenan observed increase in the RE corresponds to a decrease in thebackground tone.

FIG. 9 illustrates, by way of example and not limitation, an embodimentof a response extractor 900 configured for use to analyze an evokedresponse to detect subtle, inconsistent changes in the evoked response.The response extractor may be implanted within the patient or beexternal to the patient. The response extractor may be used in a systemthat stores and reports data from the response extractor for use inmonitoring autonomic health. In some embodiments, by way of example, theresponse extractor may be used in a system that performs an automatic orsemiautomatic titration of ANS therapy.

The response extractor 900 may include a parameter value sampler 901configured to receive sensed physiological signal(s) from physiologicalsensor(s) used to sense evoked response(s) to ANS. Examples of suchsensors include heart rate sensors, respiration sensors, blood pressuresensor, and electrocardiogram sensors. The parameter value sampler 901may, by way of example, be used to detect R-R interval values forsample(s) of the physiological signal(s). The parameter value sampler901 may derive other values such as rate variability values (e.g. heartrate variability (HRV) or respiratory rate variability (RRV)) for use indetecting the subtle, inconsistent physiologic response. Variousembodiments may monitor changes in contractility, such as may be used tomonitor Cardiac Contractility Modulation (CCM). CCM applied with aregular ON/OFF cycle may be detected if CCM changes contractionintensity or rate either directly or through a neuro mechanism.

Some embodiments may monitor patient condition and/or time The data mayfrom the physiological sensor(s) be tagged with the patient conditionsor activity or time. The data from the physiological sensor(s) may bestored with the tagged condition or tagged time. This information may betrended or otherwise analyzed to provide additional insight into theevoked response and autonomic health. Furthermore, this information maybe used to allow a clinician, or patient or other caregiver, to adjusttherapy. Some system embodiments may configured to provide automatic orsemi-automatic therapy adjustments based on this information. By way ofexample, a semi-automatic therapy adjustment may automatically proposetherapy parameters that can be adjusted by a clinician beforeimplementing, or that can be implemented by a clinician withoutadjustment.

The parameter value sensor may sample values from the sensedphysiological signal(s). If the signal(s) are digital, the sampler mayextract all digital values or a representative sampling of the signalsthat still provides the desired resolution. The sample time may but neednot correspond to the burst interval of an intermittent neuralstimulation. Some embodiments may only sample during a window of time.The sample time may be a sample (e.g. ER sample or NE sample) withinwindow(s) of time controlled by NS events (e.g. beginning of a train ofbursts in an intermittent neural stimulation therapy). The sample of ERvalues may include a sample of SE values, a sample of RE values, or botha sample of SE values and a sample of RE values. The reference valuesmay include NE values, or NE values and ER values. For example, an NSevent may identify the beginning of burst of neural stimulation pulses.This may be used to trigger sensing for a period of time during whichthe signal(s) are expected to show a direct effect and reflex effect.For example, if a 10 second burst of stimulation is provided, the windowmay be about 15 to 25 seconds to capture the direct effect (about 10seconds) and reflex effect (additional 5-15 seconds after the directeffect).

The values from the parameter value sampler 901 may be stored in astorage 902. The storage 902 may be memory in an internal or externaldevice. Further the storage may be local or remote to the parametervalue sampler. The values may be stored without distinguishing betweenthe first and second populations, and then later processed to extractthe first and second population data. In some embodiments, the parametervalue sampler distinguishes between the first population and the secondpopulation, and the storage distinguishes between the first populationdata and the second population data. The first population data mayinclude, among other types of data, evoked response (ER) valuescorresponding to the evoked physiological responses. The secondpopulation data may include, among other types of data, may includereference values that include no effect (NE) values corresponding totimes without an evoked physiological response.

The response extractor 900 may include a parameter value analyzer 903 toprovide ER scores based on the first and second population data. The ERscores quantify a relationship between the first population data and thesecond population data, and may use statistical analysis to quantify therelationship. The relationship may be converted to a standard score,such as may promote further analysis to detect subtle and/orinconsistent physiological responses. For example, the parameter valueanalyzer may be configured to quantify a statistical difference betweenthe ER values and the reference values. The response extractor 900 mayinclude a storage to store the ER scores 904. The storage 904 may bememory in an internal or external device. Further the storage may belocal or remote to the parameter value sampler. The storage 904 may beseparate with respect to or may be integrated with storage 902.

The response extractor 900 may include an ER score analyzer 905 toanalyze a group of ER scores to detect subtle, inconsistent responses.In some embodiments, the response extractor 900 may communicateinformation for use to store, report, display ER scores and other datauseful for consideration by a clinician or other caregiver or patient totitrate the stimulation. In some embodiments, the response extractor maycommunication information for use in automatically or semiautomaticallytitrate the stimulation. “Semiautomatic” indicates that some processesare automatically performed, and others are triggered or manuallyperformed. Thus, an example of a semiautomatic process may involveautomatically providing a suggested change for titrating thestimulation, and then implementing the change in response to amanually-provided confirmation from the user.

The response extractor may be contained within a single device (e.g.external device or internal device), or may be distributed into two ormore devices (e.g. two or more of internal device(s), externaldevice(s), network device(s)).

FIG. 10 illustrates an example of a system that includes an autonomichealth monitor. The illustrated autonomic health monitor 1006 mayinclude an ANS dose delivery system 1007 configured to deliverelectrical pulses to an autonomic target for an ANS dose, and mayfurther include a response extractor 1000, which may be the same orsimilar to the response extractor 900 in FIG. 9. The ANS dose deliverysystem 1007 delivers the dose to the physiology in order produce theresponse that is to be extracted by the response extractor 1000. Thedose may be delivered to through electrodes, and the response may bedetected using sensor(s). Such a monitor may be implantable or externalto the patient.

FIG. 11 illustrates an example of a system that includes an implantablemedical system 1108 and an autonomic health monitor 1106. Theimplantable medical system 1108 may include an electrical therapydelivery system 1109 such as, by way of example and not limitation, aneurostimulator or a myocardial stimulator. The autonomic health monitormay include an ANS dose delivery system 1107 configured to deliverelectrical pulses to an autonomic target for an ANS dose, and mayfurther include a response extractor 1100. The ANS dose delivery system1107 may be separate from the electrical therapy delivery system 1109.The dose may be delivered separately from any therapy delivered by theelectrical therapy delivery system 1109. The autonomic health monitor1106 may be an external device.

FIG. 12 illustrates an example of an implantable medical system 1208that includes an electrical therapy delivery system 1209 and anautonomic health monitor 1206. The electrical therapy delivery system1209 may be, by way of example and not limitation, a neurostimulator ora myocardial stimulator. The autonomic health monitor may include an ANSdose delivery system 1207 configured to deliver electrical pulses to anautonomic target for an ANS dose, and may further include a responseextractor 1200. The ANS dose delivery system 1207 may be separate fromthe electrical therapy delivery system 1209. The dose may be deliveredseparately from any therapy delivered by the electrical therapy deliverysystem 1209.

FIG. 13 illustrates an example of an implantable medical system, similarto the system illustrated in FIG. 12 that includes a cardiac rhythmmanagement system 1309 and the autonomic health monitor. The cardiacrhythm management system 1309 may configured to deliver myocardialstimulation as part of a bradycardia pacing therapy, anti-tachycardiapacing therapy, a cardiac resynchronization therapy (CRT), or adefibrillation or cardioversion therapy.

FIG. 14 illustrates an example of an implantable medical system similarto the system illustrated in FIG. 12 that includes a neurostimulationsystem 1409 and the autonomic health monitor. The neurostimulationsystem 1409 may configured to deliver a neurostimulation therapy such asan ANS therapy. Examples of ANS therapies include, but are not limitedto, heart failure and hypertension therapies. The neurostimulation maybe delivered to a neural target such as, but not limited to, a vagusnerve, a carotid sinus nerve, a glossopharyngeal nerve, a baroreceptorregion or a chemoreceptor region. Heart rate, by way of example, may bemonitored using an electrode stub or electrodes on an implantablehousing, or electrodes on or near the heart. The baroreceptor region, byway of example, may include carotid sinus baroreceptors or may includepulmonary artery baroreceptors.

FIG. 15 illustrates an example of an implantable medical system thatincludes a neurostimulation system 1509 and the autonomic health monitor1506 that share an ANS dose delivery system 1507. The ANS dose deliverysystem may be used to control the dose for the neurostimulation therapy.The ANS dose used to monitor the autonomic system may be the same doseas that used to deliver the neurostimulation therapy or may be adifferent dose.

FIG. 16 illustrates an example of a system that includes an autonomichealth monitor that uses a response extractor 1600 configured to compareresponses to trend responses. FIG. 17 illustrates an example of a methodperformed by the response extractor 1600 in FIG. 16. As represented at1710, the response extractor may be used to score evoked response valuesincluding a first evoked response value at a first time and scoring asecond evoked response value at a second time. As represented at 1711,he evoked response scores may be compared to a reference or to eachother, or may be trended. The autonomic health status may be identifiedusing the compared or trended evoked response scores, as represented at1712.

FIG. 18 illustrates an example of a system that includes an autonomichealth monitor that includes an ANS dose delivery system 1807 with adose adjustment routine 1813, and that includes a response extractor1800 to identify a response threshold 1814. The dose adjustment routine1813 may be a programmed routine that steps through different dose orintensity steps (e.g. ramp up or ramp down). The response extractor 1800is configured to identify the dose threshold where the responsesignature is first present. As identified with respect to FIG. 2,subtle, inconsistent responses toward the right side of the figure maybe detected quicker than the subtle, inconsistent responses toward theleft side of the figure. The amount of time to record data may depend onhow subtle and inconsistent the responses are. Some embodiments may usedifferent ANS doses with one dose to provide a quicker indicator of ANSresponse and another dose to provide a slower indicator of ANS response.FIG. 19 illustrates an example of a method performed by the responseextractor 1800 in FIG. 18. At 1915, a dose adjustment routine isperformed to step through multiple doses. An evoked response value isscored for each does step 1916, and the dose step is identified when thesignature is detected 1917.

FIGS. 20A-20C illustrate some Venn diagrams for the first populationdata and the second population data. The first population data includesat least some ER values but may include other values as well. The secondpopulation data includes at least some NE values but may include othervalues as well. FIG. 20A illustrates that the first and secondpopulation data sets may be mutually exclusive. FIG. 20B illustratesthat the first and second population data sets may include some datapoints that are in both the first and second population data. FIG. 20Cillustrates that the second population data set is greater than andencompasses the entirety of the first population data. The firstpopulation data may include but is not limited to ER values, and thesecond population data may include but is not limited to NE values suchthat the second population data can function as reference values againstwhich the first population data can be compared. Although the comparisonmay be made with more resolution if the first population data onlyincludes ER values and the second population data only includes NEvalues, a meaningful comparison may be made even if the first populationdata includes some NE values and/or the second population data includesER values.

FIG. 21 illustrates an example of first population data and the secondpopulation data that may be extracted from a sensed physiological signalduring intermittent neural stimulation. The illustrated example of aresponse waveform is similar to the example of a waveform illustrated inFIG. 6B, and illustrates SE values, RE values, ER values where ER valuesinclude SE and RE values, and NE values. The first population data mayinclude at least some SE values, or may include at least some RE values,or may include at least some SE and RE values. The second populationdata may include at least some NE values, or may include at least someNE values and some ER values. The population data may be but need not becontiguous data points from the sensed physiological signal. Forexample, the sensed signal may be sampled at different points during theperiod of the signal. In another example, a window may be defined for aportion of the period of the signal, and the sensed signal may besampled within the window for one or more periods that may but need notbe consecutive periods. In another example, the ANS therapy may beinterrupted to provide a time within which to sense NE values. Theseinterruption periods may be scheduled or triggered sufficiently often tomaintain accurate reference values against which the ER values may becompared. In some embodiments, the neural stimulation may beintermittent neural stimulation and the reference values may be sampledto sense NE values between bursts of the intermittent neuralstimulation.

The response extractor may use statistical techniques to quantify theevoked response value(s) against the reference values. For example, anindividual evoked response value may be compared to reference values.The evoked response value may be a mean value of two or more evokedresponse values, and the reference values may be a mean value ofreference values. The mean values may be a running average of a numberof values to smooth out the quantified revoked response values. Forexample, the mean of values 1-5 may be determined, then the mean ofvalues 2-6, and then the mean of values 3-7, etc. Again, these valuesmay be from one or more periods of the sensed physiological signal.

Statistical techniques may be used to convert the measured responsesinto a standard form to describe measures within a distribution. Twoexamples of standardized forms are Z-scores and T-scores. Z-scorestransform individual data points into a standard form, where thetransformation is based on knowledge about the population's mean andstandard deviation. Transforming raw scores to Z-scores does not changetheir distribution. T-scores transform individual data points in asample of data points into a standard form where the conversion is madewithout knowledge of the population's mean and standard deviation. Thescores are calculated using the mean and standard deviation of thesample as an estimate of the population's mean and standard deviation.By way of example, Z-scores may be used when the sample size issufficiently large to provide a meaningful means and standard deviationcalculations, and T-scores may be used for the smaller sample sizes.Thus, whether data points are scored using a Z-score or a T-scoredepends, among other things, on whether the data points represent thepopulation or a sampling of the population which depends on whether theunderlying data is considered to be the population or a sampling of thedata.

Various embodiments may use statistical techniques to calculate anevoked response metric (ERM) to quantify the difference in a firstpopulation (with evoked response values) and a second population (withNE values). The statistical technique(s) may be used to detect responsesthat are subtle and/or inconsistent. A stronger response may be evidentin a more consistent response. The first population may be taken from afirst period of time and the second population may be taken during asecond period of time. The ERM may be calculated as follows:

${ERM} = \frac{{f\left( {{First}\mspace{14mu}{{Pop}.\mspace{11mu}{Data}}} \right)} - {f\left( {{Second}\mspace{14mu}{{Pop}.\mspace{11mu}{Data}}} \right)}}{V\left( {{First}\mspace{14mu}{and}\mspace{14mu}{Second}\mspace{14mu}{{Pop}.\mspace{11mu}{Data}}} \right)}$where f represents a function such as but not limited to mean, variance,maximum, minimum, 25^(th) percentile (P25), 75^(th) percentile (P75)),and where V represents a variability function (such as Standard Error orStandard Deviation). The first and second period of times may bemutually exclusive. The first period of time may be a subset of thesecond period of time. The first and second population data sets may bemutually exclusive or may include some data points that are in both thefirst and second population data. The second population data set may begreater than and encompass the entirety of the first population data.The first population data may include but is not limited to ER values,and the second population data may include but is not limited to NEvalues such that the second population data can function as referencevalues against which the first population data can be compared. Thevariability (V) of the first and second population data may berepresented as a union of the first population data and the secondpopulation, such that data points found in both the first and secondpopulation data are present only one time in determining the variabilityso as not to provide extra weight to those data points found in both thefirst and second population data.

Using a 10 second ON 50 second OFF intermittent neural stimulation toprovide a burst period of 60 seconds, by way of example and notlimitation, some examples of ERM statistics that may be used include,but are not limited to, ERM₁, ERM₂ and ERM₃ as provided below.

${ERM}_{1} = \frac{{{Mean}\left( {{ER}{\mspace{11mu}\;}{values}\mspace{14mu} 1\mspace{14mu}{\sec.{per}.}} \right)} - {{Mean}\left( {{values}\mspace{14mu}{entire}\mspace{14mu} 60\mspace{14mu}{\sec.}} \right)}}{{Standard}\mspace{14mu}{{Deviation}\left( {{values}\mspace{14mu}{during}\mspace{14mu}{entire}\mspace{14mu} 60\mspace{14mu}{\sec.{tr}.{per}.}} \right)}}$where the first population data is a sample of values within a 10 secondstimulation ON window of time within the burst period, the secondpopulation data is the values throughout the burst period, and thevariability is determined using values throughout the burst period. Thefunction applied to the first population and the second population is a“mean” function, and the variability is a standard deviation of thevalues.

${ERM}_{2} = \frac{\begin{matrix}{{{Mean}\left( {{ER}{\mspace{11mu}\;}{values}\mspace{14mu} 10\mspace{14mu}{\sec.{per}.}} \right)} -} \\{{Mean}\left( {{values}\mspace{14mu}{remaining}\mspace{14mu} 50\mspace{14mu}{\sec.}} \right)}\end{matrix}}{{Standard}\mspace{14mu}{{Error}\left( {{values}\mspace{14mu}{during}\mspace{14mu}{entire}\mspace{14mu} 60\mspace{14mu}{\sec.{tr}.{per}.}} \right)}}$where the first population is the values during the stimulation ONportion, the second population data is the values during the stimulationOFF portion, and the variability is determined using values throughoutthe burst period. The function applied to the first population and thesecond population is a “mean” function, and the variability is astandard deviation of the values.

${ERM}_{3} = \frac{{P\; 25\left( {{ER}{\mspace{11mu}\;}1\; 0\mspace{14mu}{\sec.{per}.}} \right)} - {P\; 25\left( {{values}\mspace{14mu}{remaining}\mspace{14mu} 50\mspace{14mu}{\sec.{tr}.{per}.}} \right)}}{{Standard}\mspace{14mu}{{Error}\left( {{values}\mspace{14mu}{during}\mspace{14mu}{entire}\mspace{14mu} 60\mspace{14mu}{\sec.{tr}.{per}.}} \right)}}$where the first population is the values during the stimulation ONportion, the second population data is the values during the stimulationOFF portion, and the variability is determined using values throughoutthe burst period. The function applied to the first population and thesecond population is a “P25 (25^(th) percentile)” function, and thevariability is a standard deviation of the values. ERM₁ is a Z-statisticand ERM₂ is a t-statistic. ERM₃ does not have a common name, but is anexample of modifications that may be made to provide a useful metric forevaluating evoked response signatures. It is again noted that these areexamples. For example, the first period is not necessarily limited toperiods in which stimulation is present. ERM may be calculated at anytime to determine if the beats under consideration are different fromthe beats around them or other reference beats. In a further example, anERM may be calculated for each second in each trial, and not just duringthe duration of the stimulation burst (e.g. 10 second ON period oftime).

The output from the response extractor may be used to determine adesirable pulse amplitude for the VST. A desirable pulse amplitude for afirst VST may be used in a second VST. By way of example, a system maybe configured to deliver neural stimulation using different therapymodes to sense values that may be used to detect a subtle physiologicresponse. For example, the first therapy mode may deliver 1 or morepulses times to every cardiac cycle, and the second therapy mode maydeliver intermittent neural stimulation with scheduled burst times. Forexample, the first therapy mode (e.g. a pulse or pulses every cardiaccycle) may be delivered, and then the system may be switched to a secondtherapy mode (e.g. intermittent neural stimulation where each burst islonger than a cardiac cycle and successive bursts are separated by atime without stimulation that is also longer than a cardiac cycle). TheNE values may be sensed to provide reference values during a time ortimes between neural stimulation bursts in the second therapy mode, andthe ER values may be sensed during one or more bursts. The pulseamplitude that causes a desired subtle response during the secondtherapy mode, as determined using the ER values and the referencevalues, may be identified and used to as the pulse amplitude during thefirst therapy mode.

FIG. 22 illustrates, by way of example and not limitation, an embodimentof a response extractor with optional features to enable or disable theresponse extractions and optional features to correlate an extractedresponse to a patient status or condition. The illustrated responseextractor 2200 may function to provide an ANS therapy responseextraction process that samples parameter values, analyzes parametervalues to score ER value to reference values, and analyzes a group of ERscores to detect subtle and/or inconsistent physiologic response(s). Byway of example, the response extractor 2200 of FIG. 22 may be configuredto enable and/or disable at least part of the response process based ondetected condition 2218. Thus, for example, a system that includes theresponse extractor 2200 may be configured to use sensed heart rate,sensed activity and/or sensed posture to detect a disabling conditionthat can disable all or any part of the response process. For example,in response to a detected high activity that may cause the sensedphysiological signals to be unusually high, the parameter value sampler,or the parameter value analyzer, or the ER score analyzer, or anycombination therapy may be disabled to avoid a potential false detectionof a subtle and/or inconsistent physiological response. By way ofexample, the response extractor may be configured to enable the responseprocess in response to a detected condition that is desirable to providegood, relatively stable, underlying signals to detect the subtle and/orinconsistent physiological response.

Furthermore, by way of example, a system that includes the responseextractor may detect a patient status or detect a patient condition2219. Examples of a status or condition may include a daily or hourlyaverage, such as a mean heart rate or mean blood pressure, that mayaffect the ER scores. Examples of a status or condition may include arunning average (e.g. an average of the period of time such as the lasthour). The extracted response from the response extractor 2200 may becorrelated 2220 to the detected patient status or patient condition2219. Thus, for example, changes in a subtle and/or inconsistent heartrate effect (HRE) may be correlated to changes in the mean heart rate.This correlation may be stored, reported or displayed for use by aclinician or other user to monitor autonomic health, and in someembodiments titrate a therapy. The correlations may also be used toprovide automatic or semiautomatic titration.

FIG. 23 illustrates, by way of example, a method for titrating VST usinga subtle physiologic response. An autonomic neural stimulation (ANS)therapy may be delivered at 2321. For example, the ANS therapy may bedelivered using a nerve cuff or an intravascularly-fed electrode(s) orelectrode(s) placed adjacent the target nerve. The ANS therapy mayinclude VST. The VST may target the cervical vagus nerve. The VST maytarget the vagus nerve in other locations, such as but not limited to,cardiac nerves near the heart or vagal nerves passing by the pulmonaryartery(ies). The ANS may target cardiac fat pads. The ANS may targetneural targets in and around the carotid sinus such as baroreceptorregions, chemoreceptor regions, the carotid sinus nerve and theglossopharyngeal nerve. The ANS may target neural targets in or near thespinal cord, including the spinal cord, nerve roots, and peripheralnerves extending from the nerve roots. At 2322, physiologicalparameter(s) that may be affected by the ANS therapy are recorded. Theparameter(s) may include first population data and second populationdata as described previously. The population data may be separated intothe first and second population data and stored separately, or may begrouped together, and then processed later to separate the stored datainto first and second population data. At 2323, the data may beprocessed to score ER values (e.g. first population data) with respectto reference values (e.g. second population data). The scoring may beused to quantify a relationship between the ER values and the referencevalues or an estimate of the relationship. At 2324, a group of ER scoresmay be analyzed to detect the subtle physiological response. Forexample, the analysis of the group of ER scores may reflect a desiredsignature that is associated with an effective therapy.) The group of ERscores may be plotted or trended for use in detecting the subtlephysiological response. The group of ER scores may be combined toquantify the subtle physiological response.

FIG. 24 illustrates, by way of example, a method for monitoringautonomic health using a subtle physiological response to an ANS dosedetected using a calculated score. The ANS (e.g. VNS) may be deliveredat 2421. R-R intervals maybe recorded at 2422, allowing the heart rateto be derived therefrom. Evoked response (ER) R-R intervals andreference R-R values may be recorded. At 2423, a score may be calculatedfor the ER R-R values to quantify a comparison of the ER values to thereference values, and a group of scores may be analyzed for a signature2424. For example, statistical techniques may be used to quantify thiscomparison to provide a score. The population data points (e.g. R-Rvalues) may be processed to remove spurious data or other data that isconsidered to be noise. For example, it may be possible to furtherrefine the quantification of ER values to reference values by being moreselective in the data that is used to quantify ER values to referencevalues. The data may be collected only during a window of time aftertherapy begins (e.g. after 10 days or other beginning time period andbefore 50 days or other ending time period). Additionally oralternatively, the data may be collected only during certain windows oftime within the burst periods. Additionally or alternatively, the datamay be collected only when certain conditions are met (e.g. one or moreof mean heart rate, activity, posture, time of day, or other conditionis/are within an acceptable range).

The process for detecting R-R intervals may include detecting R peaksand band pass filtering with a cut-off frequency (e.g. 30 Hz, 200 Hz) toremove any DC component, low frequency oscillations and high frequencynoise. This filtered signal may then be scored (e.g. Z-score). A Z-scorecan be found by subtracting the mean of the entire period andnormalizing by the standard deviation of the entire period. The Z-scoredECG signal may be rectified to convert negative R peaks into positivepeaks. Local maxima may be found using a threshold, and spurious maximamay be removed to allow only one maxima within a window of time forwhich it is unlikely that two R peaks would be present. The resultingsignal may be normalized, and converted into a heart rate signal (r(t)).

${r(t)} = \frac{1}{\left( {t_{i} - t_{i + 1}} \right)}$

The heart rate signal may segmented into segments or groups (e.g. lessthan 2 interpulse periods or one burst period). For example, the heartrate signal may be segmented into 60 second groups corresponding to oneburst period for intermittent ANS delivered using 10 second ON and 50second OFF stimulation protocol.

${r(t)} = {\frac{1}{t_{i} - t_{i + 1}}{\forall{t_{i} \leq t \leq t_{i + 1}}}}$r_(j)(t) = r(t + 60j)∀0 ≤ t ≤ 60  secondswhere j represents a trial corresponding to the segment1. The z-scorecan be calculated for data points at time t within the segment (trial).

${z\left( {t,j} \right)} = \frac{{r_{j}(t)} - {\overset{\_}{r_{j}}(t)}}{{std}\left( {r_{j}(t)} \right)}$Examples of a signature may be seen below.

FIG. 25 illustrates, by way of example, a method for monitoringautonomic health using a subtle physiological response to an ANS dosedetected using an evoked response metric. The ANS (e.g. VNS) may bedelivered at 2521. Physiological parameter(s), such as heart rate, bloodpressure, respiration or variability parameters based on heart rate,blood pressure and respiration rate may be recorded at 2522. Evokedresponse values (part of a first population data) and reference values(part of second population data) may be recorded. At 2523, an evokedresponse metric (ERM) may be calculated to quantify a comparison of theER values to the reference values. Various embodiments may usestatistical techniques to calculate the ERM to quantify the differencein a first population (with evoked response values) and a secondpopulation (with NE values).

Some embodiments may record an electrocardiogram (ECG) (e.g. a P wave, aQ wave, an R wave and an S wave within the cardiac cycle). The QRS wavesmay be referred to together as a QRS complex. The ECG may be recordedusing external electrodes or internal electrodes. Some embodiments senseECG using electrodes on a can of an implantable device. The PQRSmorphology can be analyzed and a change in the PQRS morphology can becalculated to reflect the change from a time before the VNS therapy andduring the VNS therapy. An effective therapy can be associated with adesired PQRS morphology change that can serve as a template. Theillustrated method checks determine if a current change in PQRSmorphology corresponds to the template for the desired PQRS morphologychange associated with the effective therapy, and titrates the VNS (orANS) in an effort to cause the PQRSA morphology change to be closer tothe template. The process can be repeated until the PQRS change matchesor nearly matches the template for a desired PQRS change that isassociated with an effective therapy. Fiducial marks on the PQRSwaveforms may be used to detect the change in the PQRS waveform. Forexample, a difference between a P fiducial for a pre therapy waveformand a waveform during therapy delivery may provide a change in P forcomparison to the template. Similarly the differences for a Q fiducial,an R fiducial and an S fiducial can be determined for the pre therapywaveform and the waveform during therapy delivery. A match may bedetermined if change in the fiducial is sufficiently close (within athreshold) of the corresponding fiducial in the template. More marks forcomparison may correspond to a better resolution determining a match.

When VNS is delivered for 10 sec every 60 sec, acute effects on HR maybe seen, including a stimulation effect (SE) where HR is acutely loweredfor about 10 sec during the stimulation burst, and a rebound effect (RE)where HR is increased for approximately 10 sec following SE.

FIGS. 26A and 26B illustrate, by way of example, a heat map (z(t,j,0.01)) of Z-scores for a plurality of trials over a number days thatprovides a visual illustration of a signature for a stimulation effect(SE) and rebound effect (RE), and further illustrates Z-scores atdifferent points along the physiological waveform during the trial. Thefunction (z(t,j, 0.01)) refers to a filtered version of z(t,j). By wayof example, the filtered version may have a cut-off frequency such as acut-off frequency of 0.01 (or an average over 100 trials). The heat mapmay be displayed using multiple colors to show the gradation ofZ-scores. A Z-score identifies the difference between a current datapoint and the mean using standard deviation. Thus, a Z score of “1”indicates the score has a value that is one standard deviation higherthan the mean, and a Z score of “−1” indicates the score has a valuethat is one standard deviation less than the mean. In the illustratedexample, VNS was not delivered during the first several days (e.g. 7days) and was stopped after about 50 days. The trial period correspondsto the 60 second burst period for the intermittent stimulation, suchthat each day has 24 hr×60 min/hr=1440 trials per day. The SE time,illustrated within Trial 2 for FIG. 26B, indicates that the Z-scorewithin this time frame is between −1 and −2. The RE time, illustratedwithin Trial 3 for FIG. 26B, indicates that the Z-score within this timeframe is between 0.5 and 1.5 The NE time, illustrated in Trial 4 forFIG. 26B, illustrates that the Z-score within this time frame has asmall magnitude (e.g. 0-0.5). The heat map illustrated in FIG. 16Aillustrate a signature for the SE and a signature for the RE within aburst period. Various embodiments adjust the ANS to cause the signatureto match a desired signature that is effective for a given therapy (e.g.heart failure or hypertension). By way of example and not limitation, adesired subtle response may be identified using a magnitude of thechange, or a direction of the change, or a percent time that the changesare detectable, or the presence of absence of a reflex effect (RE), or acombination of these factors (e.g. significant Z-score but with aminimal magnitude of change).

FIGS. 27A-27C illustrate additional examples for quantifying acomparison between the SE and the reference values. In theillustrations, the SE values are lower than the RE values (FIG. 27A),the magnitude of the difference for the SE is larger than the RE values,and the variability increases during the times of the evoked response,which includes both the SE and RE values. FIG. 27A illustrates heartrate (HR) as a function of time calculated by averaging over trial (TR),SE and RE zones. FIG. 27B illustrates a heart rate (HR) differencebetween a trial (TR) and stimulation effect (SE), and a HR differencebetween a reflex effect (RE) and trial (TR). FIG. 27C illustrates HRV,in beats per minute, for a trial and HRV for no effect (NE).

Template profiles may be used to create several biomarkers. Biomarkersmay be used to provide a reference for monitoring autonomic health.Biomarkers may be used to identify an effective ANS therapy such as butnot limited to average, acute, chronic magnitude of TR, SE, RE, TR-SERE-TR HR and NE, TR HRV, magnitude of high, low, very low, very verylow, very very very low frequencies HRV.

FIG. 28 illustrates, by way of example, ANS dose timing to provideanother way in which the first and second population data may becaptured. The illustrated ANS dose includes intermittent stimulationduring 4 trials (burst periods), followed by 6 trials (burst periods)without neural stimulation. The first population data may be takenduring one or more of the first 4 trials which include neuralstimulation bursts, and the second population data may be taken duringone or more of the subsequent 6 trials which do not include neuralsimulation bursts.

Some embodiments may titrate the ANS dose to determine a smallest dosemagnitude that can still provide a detectable physiological effect. Someembodiments may adjust the timing in which the first and secondpopulation data is collected. For example, the first population data maychange from data during the stimulation burst to during the stimulationburst and some time after the stimulation burst. Some embodiments mayadjust the trial length from being the same as the burst period (e.g. 60seconds) to a length greater the burst period, but may still be lessthan two burst periods. Thus, for example, NE values may be detected forsome time before and after ER values. Some embodiments may score the ERvalues to look for acute effects (e.g. burst to burst effects). Someembodiments may look for chronic changes by turning on ANS for a longerperiod of time (e.g. 5 to 20 minutes) in which first population data maybe recorded and off for a longer period of time (e.g. 5 to 60 minutes)in which second population data may be recorded to look for a signaturein the relationship between the first and second population data.

A device may capture data using various techniques. For example, sensedphysiological data may be stored, and data marks or time marks may beadded for use to identify when simulation is applied. Some embodimentsmay store the raw data (e.g. R-R intervals). Some embodiments onlyrecord a sample size needed to detect the signature. Thus, for example,if the signature is present for a given percentage of time, then one canexpect to detect that signature after so many trials.

Some embodiments may monitor a percentage of time that a detectablesignature is present. For example, when the signal is detected a greaterpercentage of time, then one may conclude that the underlying backgroundof autonomic activity is changing. For example, when the stimulation isa vagal stimulation and the signal is detected a greater percentage oftime, one may conclude that the underlying background is becoming moresympathetic. When the stimulation is a vagal stimulation and the signalis detected a smaller percentage of time, one may conclude that theunderlying background is becoming less sympathetic.

The response monitor may be remotely managed and programmed. Thus, forexample, a patient may wear external ECG electrodes to collect datawhile they are away from a clinical setting. Patient conditions oractivities or time may also be monitored. The ECG data may be taggedwith the patient conditions or activity or time. For example, the ECGdata may be stored with data indicating if the ECG data was collectedfor a particular patient posture or a particular patient activity or aparticular time of day.

FIG. 29 illustrates, by way of example, an embodiment of a system thatincludes an ANS dose delivery system 2925, a dose response monitor 2926,and an external device 2927. The external device 2927 may have a userinterface, of which a component may be a display 2928. The display maybe a touch screen display. The display may output information to theuser (patient, or clinician or other caregiver), for use in monitoringautonomic health. For example, as illustrated at 2929, the display mayoutput the quantified relationship (e.g. calculated ERM) between thefirst and second population data. The display may output a trend ofscores (e.g. ERM scores) 2930. The display may illustrate or otherwiseidentify the make-up of the first and second population data 2931. Forexample, the display may identify whether the first and secondpopulation data are exclusive sets of data, if they have a union of datapoints, or if one set encompasses all of the other set. The display mayidentify the relative position of the first and/or second populationdata with respect to the neural stimulation bursts (e.g. coextensivewith the bursts, during a portion of the burst, over the course of 4burst periods, etc.). The display may also provide an indication of theresponse monitor calculation 2932. For example, recommended programmingchanges and/or potential programming changes may be made based on thereported scores. The display may also identify the function applied tothe population to determine the ERM scores, and/or identify potentialfunctions that may be applied to the population.

FIG. 30 illustrates a system embodiment configured to extract an evokedresponse and control stimulation using the extracted response. Variousdevice embodiments include an ANS dose delivery system 3025, a doseresponse monitor 3026 (which may be similar to the response monitor 2926in FIG. 29) with a response extractor 3000 (which may be similar to theresponse extractors in previous figures) that is capable of providingfeedback from sensors 3033 (e.g. HR sensor). The ANS dose deliverysystem 3025 may also be configured to delivery an ANS therapy inaddition to delivering an ANS dose for use in monitoring autonomichealth. Examples of ANS therapy include neural stimulation to the vagusnerve (VNS), carotid sinus nerve, glossopharyngeal nerve, baroreceptorregions, chemoreceptor regions, spinal cord, and nerve roots. The ANStherapy can directly or reflexively modulate heart rate, for example.The response extractor 3000 can extract a representation of the evokedresponse by determining how the heart rate and/or blood pressureresponse during times of stimulation (e.g. a burst of neural stimulationpulses) compares to the responses during times without stimulation. Thecontroller 3034 may be configured to modulate the neurostimulation dose3035 (e.g. charge delivered over a period of time) and/or duty cycle3036. The controller 3034 may control the pulse generator 3037 tocontrol the pattern of pulses delivered to the patient. In someembodiments, the pulse generator 3037 or controller 3034 may provide amarker (“NS Event” marker) to the response extractor for use to time thestart and stop times for recording physiological data.

The effect of the neural stimulation on HR or BP may controlled by theNS dose, which consists of a complex set of variables, includingelectrode design, stimulation site, pulse amplitude, width and phase,pulse burst duration and pattern, stimulation timing, and the like. Theselection of NS dose may depend on the therapeutic application of thedevice. In some applications, the NS dose may be selected to decrease orincrease HR or BP by directly stimulating neural pathways that controlHR or BP. This in turn may result in compensatory reflex changes in HRor BP after the NS event ends. In such cases, the NS event may cause anoscillation of HR or BP that lasts for several seconds or minutes. Theseare oscillatory evoked responses. They may be preferred in someapplications of the device to deliver a combination of directlystimulated and reflex changes in ANS activity. By altering the NS dose,the device can control the magnitude, pattern, and duration of theevoked responses. A device response extractor can measure these evokedresponse parameters to be used by a controller to adapt the NS dose toachieve a desired evoked response that is subtle and/or inconstant,detectable using statistical techniques to determine an ERM score.

Sensors 3033 may provide a continuous stream of signal data to theresponse extractor 300. This data stream can be digitized into adiscrete time series for analysis. The response extractor 3000 may benotified of each intermittent NS event, and use these events to recordor process the signal time series to provide the first and secondpopulation data. Multiple NS events may be analyzed to provide evokedresponse data to the controller 3034. The controller 3034 may use thisdata according to programmed parameters to control the duty cycle and/orthe dose of the neurostimulation. The controller may be programmed toadjust the NS dose until the evoked response data match programmedcriteria (signature or ERM score). The controller 3034 may providesearch parameters to the response extractor 3000 to control itsfunctions, such as to set search criteria or search windows for theextraction algorithms, or request which evoked response data are to beextracted, among other possibilities.

The illustrated system may also include dose control clock(s) 3038 tocontrol the processes performed by the system. For example, the clock(s)3038 may include dose control clock(s) for use to control the timing ofthe neural stimulation pulses delivered in the bursts of pulses, and toalso control the timing of the neural stimulation burst of pulses suchas burst start, burst stop, burst duration, or various combinationsthereof. The therapy protocol clock(s) may also control a schedule ofneural stimulation dose. Some embodiments use a timer and a programmedschedule to adjust VNS dose. The clock(s) 3038 may include a VNSsuspension clock or clocks for use to control timing of stimulationsuspensions. The stimulation suspensions may override scheduled VNStimes. For example, a patient may indicate, via remote control or otherexternal device, by “tapping” over the implantable device, by a magnet,or otherwise, a desire to suspend VNS because the VNS is not beingtolerated or because the VNS may interfere with an activity (e.g.speaking, eating, etc.). Some embodiments may, additionally oralternatively, suspend therapy for specific patient conditions. By wayof example and not limitation, the patient condition may be arespiration infection or sore throat caused by a virus or anothercondition for which a VNS may be more aggravating. The therapysuspension clock can time the temporary suspension and reengage thescheduled therapy after the suspension. The therapy suspension may betriggered by a dose monitor. For example, once the desired level ofstimulation has been delivered for a given period of time (e.g. dailydose of stimulation), then the dose monitor may suspend the therapy forthe remainder of that time (e.g. remainder of the day).

FIG. 31 illustrates a VNS system, according to various embodiments. TheVNS system is an example of an ANS system. An implantable device mayprovide the entire VNS system. Some embodiments use external devices toprovide the monitoring functions or some of the monitoring functions,such as during implantation of an implantable vagus nerve stimulator.The illustrated VNS system includes VNS response monitor 3139 and a VNStherapy and test dose delivery system 3140. It is noted that the VNSintensity for the test dose to monitor autonomic health may beindependent of the VNS intensity delivered as part of the VST.

The VNS therapy and test dose delivery system may include a pulsegenerator 3141 to provide VNS therapy, a controller 3142 configured witha modulator 3143 to change or modulate intensity of the VST and clocks3144. The system may further include a VNS response monitor 3139 toprovide feedback which may be used to allow the patient, clinician orother caregiver to program adjustments or which may be used to provideautomatic or semiautomatic programming adjustments. The autonomicnervous system is generally illustrated at 3145. Appropriateelectrode(s) 3146 are used to provide desired neural stimulation andsensor(s) 3147 to sense a parameter that is affected by the neuralstimulation. Physiological parameter(s) that quickly respond to VST canbe used in closed loop systems or during the implantation process.Examples of such parameters include heart rate, laryngeal vibration,blood pressure, respiration, electrogram parameters. Othercardiovascular parameter(s) and other surrogate parameters that have aquick and predictable response indicative of the overall response of theparasympathetic nervous system to the neural stimulation. Otherparameter(s) that have a slower response may be used to confirm that atherapeutically-effective dose is being delivered. The sensor(s) andelectrode(s) can be integrated on a single lead or can use multipleleads. Additionally, various system embodiments implement the functionsusing an implantable neural stimulator capable of communicating with adistinct or integrated implantable cardiac rhythm management device.

The VNS response monitor 3139 may include a monitor 3148, a comparator3149, and may further included a programmable targeted signature ortemplate of a subtle and/or inconsistent response 3150, and may includeprogrammable boundary value(s) 3151 that may limit the adjustmentsduring a titration routine. The illustrated monitor 3148 monitors theparameter during a time with stimulation to provide a first feedbacksignal 3152 indicative of a parameter value corresponding to a time withstimulation and during a time without stimulation to provide a secondfeedback signal 3153 indicative of a parameter value corresponding to atime without stimulation. The signals 3152 and 3153 are illustrated asseparate lines. These signals can be sent over different signal paths orover the same signal path. A comparator 3149 receives the first andsecond feedback signals 3152 and 3153 and determines a detected changein the parameter value based on these signals. Additionally, thecomparator compares the detected change with an allowed change, whichcan be programmed into the device. For example, the device can beprogrammed to allow a heart rate reduction during VST to be no less thana percentage (e.g. on the order of 95%) of heart rate withoutstimulation. The device may be programmed with a quantitative value toallow a heart rate reduction during VST to be no less than thatquantitative value (e.g. 5 beats per minute) than heart rate withoutstimulation. The monitor 3148 may include a response extractor 3100,similar to previously-described response extractors that analyzes afirst population of data that includes data during the time withstimulation and a second population of data that includes data duringthe time without stimulation. The response extractor may calculate anERM score or otherwise quantify a relation between the first and secondpopulations. The comparator 3149 may compare the ERM score from theresponse extractor (or other quantified score) to the targeted signature3150 for the subtle response and provide a comparison result to thecontroller 3142.

As illustrated, the system may be programmed with an upper boundaryvalue 3151 corresponding to a monitored parameter value used to providean upper boundary on VST intensity, and the VST response monitor 3139may include an upper boundary parameter monitor 3154. The upper boundaryparameter monitor provides a signal indicative of a sensed value for theparameter, which is compared to the upper boundary value. The VSTintensity is adjusted to be below the upper VST intensity, as detectedusing the upper boundary value and upper boundary parameter monitor. Theupper boundary value may be pre-programmed based on patient-specificresponses to VST or based on data for a patient population. Theillustrated embodiment monitors heart rate, and compares sensed heartrate to a preprogrammed heart rate corresponding to an upper boundaryfor VST intensity. The system may also be programmed with a lowerboundary value 3151 corresponding to a monitored parameter value used toprovide a lower boundary on VST intensity, and the VST response monitor3148 includes a lower boundary parameter monitor 3155. The lowerboundary parameter monitor provides a signal indicative of a sensedvalue for the parameter, which is compared to the lower boundary value.The VST intensity is adjusted to be above the lower VST intensity, asdetected using the lower boundary value and lower boundary parametermonitor. The lower boundary value may be pre-programmed based onpatient-specific responses to VST or based on data for a patientpopulation. The illustrated embodiment monitors laryngeal vibration.

Some embodiments use a therapy protocol that adjusts the VST intensity,limited by the upper boundary for the VST intensity and in someembodiments by the lower boundary for the VST intensity, to provide thetargeted signature for the subtle response. The VST intensity can beadjusted, within the allowed bounds set by the present subject matter,based on other parameters such as blood pressure, respiration, andelectrogram measurement. Some therapy protocols adjust the targetedsubtle response, and may also adjust the upper boundary and/or lowerboundary for VNS therapy intensity based on a schedule (e.g. time ofday) or sensed data (e.g. activity). Some examples of programmableparameters that may be used and modified based on an evoked response caninclude parameters used to adjust the intensity of the neuralstimulation 3156, such as amplitude 3157, frequency 3158, pulse width3159. Some embodiments adjust the neural stimulation schedule 3160 toadjust the neural stimulation intensity. Examples of schedule parameters3160 include therapy duration 3161 (e.g. how many minutes the INStherapy protocol is delivered), start/stop times 3162 (e.g. when tostart or stop the INS therapy protocol), stimulation period 3163 (e.g.the burst interval of the INS therapy protocol), stimulation trainduration per stimulation period 3164 (e.g. the burst duration of the INStherapy protocol), duty cycle 3165 (e.g. the stimulationduration/stimulation period of the INS therapy protocol), and a ramp upand/or ramp down 3166 for the intensity of the stimulation burst. Someembodiments are designed with the ability to operationally position aplurality of electrodes near the neural pathway to stimulate differentlocations along the neural pathway to initiate an action potential atthese different locations along the neural pathway. As generallyillustrated at 3167, some embodiments change where the nerve isstimulated and/or the vectors used to change the distance that theaction potential has to travel before inducing a response, and thuschanges the timing of the response induced by the action potential for adirect response or a reflex response. Some embodiments control whetheran efferent or afferent pathway is being stimulated, as illustratedgenerally at 3168. Some embodiments may change VNS intensity bytargeting different nerve fiber populations. By way of example and notlimitation, different nerve fibers may be targeted by adjusting thestimulation field by current steering and/or changing electrodes.Adjustment of these parameters may be used to adjust the evoked response(e.g. stimulation effect and reflex).

As illustrated, the system may include a patient tolerance control 3169which may be an input for responding to a patient signal or an input toreceive a signal from the system if the system can detect or derive thatthe patient is unable to tolerate the therapy. The controller mayrespond by maintaining the pulse amplitude by but reducing the overalldose by reducing other parameter(s) (e.g. frequency, or pulse width, orvarious scheduling parameters.) The neural stimulation delivered duringthe duty cycle can be delivered using a variety of neural stimulationtechniques, such as stimulation that uses electrical, ultrasound,thermal, magnetic, light (optigenetics) or mechanical energy (such asacupuncture). Electrical neural stimulation is used in this document asan example of neural stimulation. In electrical stimulation, forexample, a train of neural stimulation pulses (current or voltage) canbe delivered during a duty cycle of stimulation. Stimulation pulsewaveforms can be square pulses or other morphologies. Additionally, thestimulation pulses can be monophasic or biphasic pulses.

The illustrated system for delivering VNS therapy may useful in extendedtherapy applications. Examples of extended therapy applications involveapplying stimulation to prevent remodeling of cardiac tissue and toreverse remodel cardiac tissue in cardiovascular disease. VNS therapycan be applied for a portion (approximately 10 seconds) of each minute,for example. A VNS therapy dose may be adjusted by adjusting theduration or duty cycle of the stimulation (e.g. approximately 5 secondsor 15 seconds each minute or approximately 5 to 15 seconds every 30seconds or approximately 5 to 30 seconds every 2 minutes, orapproximately 5 seconds to 3 minutes every 5 minutes or a continuousstimulation). According to an embodiment, the VNS therapynon-selectively stimulates both efferent and afferent axons. Theillustrated values are provided by way of example, and not limitation.Over the course of days, weeks, months and years, the physiologicalresponse to VNS therapy can vary for a number of reasons, such as nerveadaptation, tissue encapsulation, fibrosis, impedance changes, and thelike. Further, the patient health and disease state may change.Additionally, the activity or other status or condition of the patientmay also change. Therefore, it is desirable to be able to quantify theevoked response of the stimulation to make adjustments that accommodatethese changes.

Open loop VST systems set the VST intensity during VST testing. This VSTtesting may be based on a relatively large human population or may beperformed during the implantation procedure. By way of example, VSTintensity for an open loop system may be titrated as follows. When VSTis turned on for the first time, the heart rate is monitored duringtesting. If there is any significant bradycardia (e.g. more than a 5%drop in heart rate) during the ON time of VST cycle, VST intensity (alsoreferred to as VST dose) will be reduced. The VST dose can be reduced byadjusting one or more VST parameters such as amplitude, frequency, pulsewidth, etc. During the follow-up office visits for therapy titration,VST parameters may be adjusted to provide a therapeutically-effectivedose at a targeted subtle therapeutic response.

FIG. 32 illustrates an implantable medical device (IMD) 3269 having aneural stimulation (NS) component 3270 and a cardiac rhythm management(CRM) component 3271 according to various embodiments of the presentsubject matter. The illustrated device includes a controller 3272 andmemory 3273. According to various embodiments, the controller includeshardware, software, firmware or a combination thereof to perform theneural stimulation and CRM functions. For example, the programmedtherapy applications discussed in this disclosure are capable of beingstored as computer-readable instructions embodied in memory and executedby a processor. For example, stimulation schedule(s) and programmableparameters can be stored in memory. According to various embodiments,the controller includes a processor to execute instructions embedded inmemory to perform the neural stimulation and CRM functions, as well asthe ANS dose delivered to monitor autonomic health. The illustratedneural stimulation therapy can include various neural stimulationtherapies, such as a heart failure therapy or a hypertension therapy.Various embodiments include CRM therapies, such as bradycardia pacing,anti-tachycardia therapies such as ATP, defibrillation andcardioversion, and cardiac resynchronization therapy (CRT). Theillustrated device further includes a transceiver 3274 and associatedcircuitry for use to communicate with a programmer or another externalor internal device. Various embodiments include a telemetry coil.

The CRM therapy section 3271 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The illustrated CRM therapy section includes apulse generator 3275 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry3276 to detect and process sensed cardiac signals. An interface 3277 isgenerally illustrated for use to communicate between the controller 3277and the pulse generator 3275 and sense circuitry 3276. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 3270 includes components, under the control ofthe controller, to stimulate a neural stimulation target and/or senseparameters associated with nerve activity or surrogates of nerveactivity such as blood pressure, heart rate and respiration. Threeinterfaces 3278 are illustrated for use to provide neural stimulation.However, the present subject matter is not limited to a particularnumber interfaces, or to any particular stimulating or sensingfunctions. Pulse generators 3279 are used to provide electrical pulsesto transducer or transducers for use to stimulate a neural stimulationtarget. According to various embodiments, the pulse generator includescircuitry to set, and in some embodiments change, the amplitude of thestimulation pulse, the pulse width of the stimulation pulse, thefrequency of the stimulation pulse, the burst frequency of the pulse,and the morphology of the pulse such as a square wave, sinusoidal wave,and waves with desired harmonic components. Sense circuits 3280 are usedto detect and process signals from a sensor, such as a sensor of nerveactivity, blood pressure, respiration, and the like. The interfaces 3278are generally illustrated for use to communicate between the controller3272 and the pulse generator 3279 and sense circuitry 3280. Eachinterface, for example, may be used to control a separate lead. Variousembodiments of the NS therapy section only include a pulse generator tostimulate a neural target. The illustrated device further includes aclock/timer 3281 or multiple clocks/timers, which can be used to deliverthe programmed therapy according to a programmed stimulation protocoland/or schedule and to suspend therapy. The controller 3272 may includea response extractor, and may also control the therapy according toprogrammable therapy dose, duty cycle, and search parameters, asdiscussed previously.

FIG. 33 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments. The controller of the device is a microprocessor 3382 whichcommunicates with a memory 3383 via a bidirectional data bus. Thecontroller could be implemented by other types of logic circuitry (e.g.,discrete components or programmable logic arrays) using a state machinetype of design. As used herein, the term “circuitry” should be taken torefer to either discrete logic circuitry or to the programming of amicroprocessor. Shown in the figure are three examples of sensing andpacing channels designated “A” through “C” comprising bipolar leads withring electrodes 3384A-C and tip electrodes 3385A-C, sensing amplifiers3386A-C, pulse generators (“stimulus”) 3387A-C, and channel interfaces3388A-C. Each channel thus includes a pacing channel made up of thepulse generator connected to the electrode and a sensing channel made upof the sense amplifier connected to the electrode. The channelinterfaces 3388A-C communicate bidirectionally with the microprocessor3382, and each interface may include analog-to-digital converters fordigitizing sensing signal inputs from the sensing amplifiers andregisters that can be written to by the microprocessor in order tooutput pacing pulses, change the pacing pulse amplitude, and adjust thegain and threshold values for the sensing amplifiers. The sensingcircuitry of the pacemaker detects a chamber sense, either an atrialsense or ventricular sense, when an electrogram signal (i.e., a voltagesensed by an electrode representing cardiac electrical activity)generated by a particular channel exceeds a specified detectionthreshold. Pacing algorithms used in particular pacing modes employ suchsenses to trigger or inhibit pacing. The intrinsic atrial and/orventricular rates can be measured by measuring the time intervalsbetween atrial and ventricular senses, respectively, and used to detectatrial and ventricular tachyarrhythmias.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 3389 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing (can) 3390 or an electrode on another lead serving as aground electrode. Some embodiments may have multiple can electrodes suchas may be used to sense electrocardiograms (ECGs). Some embodimentsprovide a shock pulse generator 3391 interfaced to the controller fordelivering a defibrillation shock via shock electrodes 3392 and 3393 tothe atria or ventricles upon detection of a shockable tachyarrhythmia.

Neural stimulation channels, identified as channels D and E, areincorporated into the device for delivering parasympathetic and/orsympathetic excitation and/or parasympathetic and/or sympatheticinhibition, where one channel includes a bipolar lead with a firstelectrode 3394D and a second electrode 3395D, a pulse generator 3396D,and a channel interface 3397D, and the other channel includes a bipolarlead with a first electrode 3394E and a second electrode 3395E, a pulsegenerator 3396E, and a channel interface 3397E. Other embodiments mayuse unipolar leads in which case the neural stimulation pulses arereferenced to the can or another electrode. Other embodiments may usetripolar or multipolar leads. In various embodiments, the pulsegenerator for each channel outputs a train of neural stimulation pulseswhich may be varied by the controller as to amplitude, frequency,duty-cycle, and the like. In some embodiments, each of the neuralstimulation channels uses a lead which can be intravascularly disposednear an appropriate neural target. Other types of leads and/orelectrodes may also be employed. A nerve cuff electrode may be used inplace of an intravascularly disposed electrode to provide neuralstimulation. In some embodiments, the leads of the neural stimulationelectrodes are replaced by wireless links.

The figure illustrates a telemetry interface 3398 connected to themicroprocessor, which can be used to communicate with an externaldevice. The illustrated microprocessor 2489 is capable of performingneural stimulation therapy routines and myocardial (CRM) stimulationroutines and is also capable of monitoring autonomic health byevaluating subtle and/or inconsistent responses to an ANS dose. Examplesof NS therapy routines include, but are not limited to, therapies toprovide physical conditioning and therapies to treat ventricularremodeling, hypertension, sleep disordered breathing, blood pressurecontrol such as to treat hypertension, cardiac rhythm management,myocardial infarction and ischemia, heart failure, epilepsy, depression,for pain, migraines, eating disorders and obesity, and movementdisorders. Examples of myocardial therapy routines, but are not limitedto, include bradycardia pacing therapies, anti-tachycardia shocktherapies such as cardioversion or defibrillation therapies (includingsubcutaneous implantable cardioverter-defibrillators), anti-tachycardiapacing therapies (ATP), and cardiac resynchronization therapies (CRT).Additional sensors (not illustrated) such as respiration and bloodpressure sensors may also be incorporated into the system for use intitrating an ANS therapy. An ANS dose routine may be performed todeliver a test dose of stimulation via stimulus 3396D or 3396E, andmonitor HR via sensing amplifiers 3386A-C.

FIG. 34 illustrates a system 3401 including an implantable medicaldevice (IMD) 3402 and an external system or device 3403, according tovarious embodiments of the present subject matter. Various embodimentsof the IMD include NS functions or include a combination of NS (e.g. ANSdose) and CRM functions. The IMD may also deliver biological agents andpharmaceutical agents. The external system and the IMD are capable ofwirelessly communicating data and instructions. In various embodiments,for example, the external system and IMD use telemetry coils towirelessly communicate data and instructions. Thus, the programmer canbe used to adjust the programmed therapy provided by the IMD, and theIMD can report device data (such as battery and lead resistance) andtherapy data (such as sense and stimulation data) to the programmerusing radio telemetry, for example. The external system allows a usersuch as a physician or other caregiver or a patient to control theoperation of the IMD and obtain information acquired by the IMD. In oneembodiment, the external system includes a programmer communicating withthe IMD bi-directionally via a telemetry link. In another embodiment,the external system is a patient management system including an externaldevice communicating with a remote device through a telecommunicationnetwork. The external device is within the vicinity of the IMD andcommunicates with the IMD bi-directionally via a telemetry link. Theremote device allows the user to monitor and treat a patient from adistant location. The patient monitoring system is further discussedbelow. The telemetry link provides for data transmission from theimplantable medical device to the external system. This includes, forexample, transmitting real-time physiological data acquired by the IMD,extracting physiological data acquired by and stored in the IMD,extracting therapy history data stored in the implantable medicaldevice, and extracting data indicating an operational status of the IMD(e.g., battery status and lead impedance). The telemetry link alsoprovides for data transmission from the external system to the IMD. Thisincludes, for example, programming the IMD to acquire physiologicaldata, programming the IMD to perform at least one self-diagnostic test(such as for a device operational status), and programming the IMD todeliver at least one therapy.

FIG. 35 illustrates a system 3501 including an external device 3503, animplantable neural stimulator (NS) device 3504 which may be used toprovide a NS dose or therapy and an implantable cardiac rhythmmanagement (CRM) device 3505, according to various embodiments of thepresent subject matter. The CRM device may be a pacemaker, acardioverter, a defibrillator, a CRT device, or a subcutaneousimplantable cardioverter-defibrillator. Various aspects involvecommunication between an NS device and a CRM device or other cardiacstimulator. In various embodiments, this communication may allow the NSdevice to deliver ANS dose to monitor autonomic health or may allow oneof the devices 2613 or 2614 to deliver more appropriate therapy (i.e.more appropriate NS therapy or CRM therapy) based on data received fromthe other device. Additionally, the sensors from the CRM device maymonitor HR, BP, or another parameter for the response to the neuralstimulation. Some embodiments provide on-demand communications. Theillustrated NS device and the CRM device are capable of wirelesslycommunicating with each other, and the external system is capable ofwirelessly communicating with at least one of the NS and the CRMdevices. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.Rather than providing wireless communication between the NS and CRMdevices, various embodiments provide a communication cable or wire, suchas an intravenously-fed lead, for use to communicate between the NSdevice and the CRM device. In some embodiments, the external systemfunctions as a communication bridge between the NS and CRM devices.

FIGS. 36-39 illustrate system embodiments adapted to provide vagalstimulation, and are illustrated as bilateral systems that can stimulateboth the left and right vagus nerve. Those of ordinary skill in the artwill understand, upon reading and comprehending this disclosure, thatsystems can be designed to stimulate only the right vagus nerve, systemscan be designed to stimulate only the left vagus nerve, and systems canbe designed to bilaterally stimulate both the right and left vagusnerves. The systems can be designed to stimulate nerve traffic(providing a parasympathetic response when the vagus is stimulated), orto inhibit nerve traffic (providing a sympathetic response when thevagus is inhibited). Various embodiments deliver unidirectionalstimulation or selective stimulation of some of the nerve fibers in thenerve, and various embodiments may deliver non-selective bidirectionalstimulation of the nerve fibers. The ANS dose may be delivered to theright and/or left vagus nerve. Those of ordinary skill in the art willalso understand, upon reading and comprehending this disclosure, thatsimilar systems may be designed to stimulate other ANS targets such as,by way of example and not limitation the carotid sinus nerve, theglossopharyngeal nerve, baroreceptor regions, and chemoreceptor regions.

FIG. 36 illustrates a system embodiment in which an IMD 3606 is placedsubcutaneously or submuscularly in a patient's chest with lead(s) 3607positioned to stimulate a vagus nerve. According to various embodiments,neural stimulation lead(s) 3607 are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget or may have electrode(s) place proximately within the carotidsheath. Some vagus nerve stimulation lead embodiments areintravascularly fed into a vessel proximate to the neural target, anduse electrode(s) within the vessel to transvascularly stimulate theneural target. For example, some embodiments stimulate the vagus usingelectrode(s) positioned within the internal jugular vein. Otherembodiments deliver neural stimulation to the neural target from withinthe trachea, the laryngeal branches of the internal jugular vein, andthe subclavian vein. The neural targets can be stimulated using otherenergy waveforms, such as ultrasound and light energy waveforms. Otherneural targets can be stimulated, such as cardiac nerves and cardiac fatpads. The illustrated system includes leadless ECG electrodes 3608 onthe housing of the device. These ECG electrodes are capable of beingused to detect R-R intervals, PQRS waveforms, or heart rate, forexample.

FIG. 37 illustrates a system embodiment that includes an implantablemedical device (IMD) 3706 with satellite electrode(s) 3709 positioned tostimulate at least one neural target. The satellite electrode(s) areconnected to the IMD, which functions as the planet for the satellites,via a wireless link. Stimulation and communication can be performedthrough the wireless link. Examples of wireless links include RF linksand ultrasound links. Examples of satellite electrodes includesubcutaneous electrodes, nerve cuff electrodes and intravascularelectrodes. Various embodiments include satellite neural stimulationtransducers used to generate neural stimulation waveforms such asultrasound and light waveforms. The illustrated system includes leadlessECG electrodes on the housing of the device. These ECG electrodes 3708are capable of being used to detect R-R intervals, PQRS waveforms, orheart rate, for example.

FIG. 38 illustrates an IMD 3806 placed subcutaneously or submuscularlyin a patient's chest with lead(s) 3810 positioned to provide a CRMtherapy to a heart, and with lead(s) 3807 positioned to stimulate and/orinhibit neural traffic at a neural target, such as a vagus nerve,according to various embodiments. According to various embodiments,neural stimulation lead(s) are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some lead embodiments are intravascularly fed into a vesselproximate to the neural target, and use transducer(s) within the vesselto transvascularly stimulate the neural target. For example, someembodiments target the vagus nerve using electrode(s) positioned withinthe internal jugular vein.

FIG. 39 illustrates an IMD 3906 with lead(s) 3910 positioned to providea CRM therapy to a heart, and with satellite transducers 3909 positionedto stimulate/inhibit a neural target such as a vagus nerve, according tovarious embodiments. The satellite transducers are connected to the IMD,which functions as the planet for the satellites, via a wireless link.Stimulation and communication can be performed through the wirelesslink. Examples of wireless links include RF links and ultrasound links.Although not illustrated, some embodiments perform myocardialstimulation using wireless links. Examples of satellite transducersinclude subcutaneous electrodes, nerve cuff electrodes and intravascularelectrodes.

FIG. 40 illustrates, by way of example, an IMD 4006 with a lead 4007positioned to stimulate and/or inhibit neural traffic at a vagus nerve,according to various embodiments. Some embodiments may use implantablesensor(s) 4011, such as ECG or respiratory sensors, to sensephysiological parameters for use in detecting the subtle and/orinconsistent physiological response. Sensed data from the implantablesensor(s) may be recorded in the IMD 4006. Some embodiments may useexternal sensor(s) 4012, such as blood pressure, ECG or respiratorysensor, to sense physiological parameters for use in detecting thesubtle physiological response. Sensed data from the external sensor(s)4012 may be recorded in an external recorder such as a wearable recorder4013. In some embodiments, the wearable recorder 4013 may communicatewith the IMD 4006. In some embodiments, the wearable recorder maycommunicate with an external system 4014 such as but not limited to aprogrammer. In some embodiments, the IMD 4006 may communicate with anexternal system 4014 such as but not limited to a programmer.

FIG. 41 is a block diagram illustrating an embodiment of an externalsystem 4115. The external system includes a programmer, in someembodiments. In the illustrated embodiment, the external system includesa patient management system. As illustrated, the external system 4115 isa patient management system including an external device 4116, atelecommunication network 4117, and a remote device 4118. The externaldevice 4115 is placed within the vicinity of an implantable medicaldevice (IMD) and includes an external telemetry system 4119 tocommunicate with the IMD. The remote device(s) 4118 is in one or moreremote locations and communicates with the external device 4116 throughthe network 4117, thus allowing a physician or other caregiver tomonitor and treat a patient from a distant location and/or allowingaccess to various treatment resources from the one or more remotelocations. The illustrated remote device 4118 includes a user interface4120. According to various embodiments, the external device 4116includes a neural stimulator, a programmer or other device such as acomputer, a personal data assistant or phone. The external device 4116,in various embodiments, includes two devices adapted to communicate witheach other over an appropriate communication channel. The externaldevice can be used by the patient or physician to provide side effectfeedback indicative of patient discomfort, for example.

Patient management systems may be used to enable the patient and/ordoctor to monitor autonomic health, and may be used to adjustparameter(s) to compensate for undesired responses, such as may besensed by physiologic parameters and output to the patient and/ordoctor. The inputs may be provided by computers, programmers, cellphones, personal digital assistants, and the like. The patient may calla call center using a regular telephone, a mobile phone, or theInternet. The communication can be through a repeater, similar to thatused in Boston Scientific's Latitude patient management system. Inresponse, the call center (e.g. server in call center) may automaticallysend information to the device to adjust or titrate the therapy. Thecall center may inform the patient's physician of the event. A deviceinterrogation may be automatically triggered. The results of the deviceinterrogation may be used to determine if and how the therapy should beadjusted and/or titrated to improve the response. A server canautomatically adjust and/or titrate the therapy using the results of thedevice interrogation. Medical staff may review the results of the deviceinterrogation, and program the device through the remote server toprovide the desired therapy adjustments and/or titrations. The servermay communicate results of the device interrogation to the patient'sphysician, who may provide input or direction for adjusting and/ortitrating the therapy.

FIG. 42 illustrates, by way of example and not limitation, an embodimentof a system, various components of which may be used to store thepopulation data and process the population data to score the data. Theillustrated system may include an implantable device 4221, an externaldevice 4222, a clinician programmer 4223, a network 4224 and server(s)4225 connected through the network. Any one or combination of thedevices may store data, and any one or combination of the devices mayprocess the data. Furthermore, by way of example, the external patientdevice 4222 and/or the clinician programmer may be connected to the sameor different storage.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the terms module and circuitry, for example, are intended to encompasssoftware implementations, hardware implementations, and software andhardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. A system may beconfigured to implement the method. The system may be configured withhardware, software, firmware, or any combination thereof to implementthe method. In various embodiments, the methods are implemented usingcomputer data in tangible media, that represents a sequence ofinstructions which, when executed by one or more processors cause theprocessor(s) to perform the respective method or at least a portion ofthe method. In various embodiments, the methods are implemented as a set(or sets) of instructions contained on a computer-accessible medium (ormedia) capable of directing a processor or other controller to performthe respective method or at least a portion of the method. In variousembodiments, the medium or media include at least one of a magneticmedium, an electronic medium, or an optical medium.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of skill in theart upon reading and understanding the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled.

What is claimed is:
 1. A method, comprising: delivering an autonomicneural stimulation (ANS) dose over a plurality of burst periods,including delivering a burst stimulation pulses within a portion of eachburst period to evoke physiological responses and not deliveringstimulation pulses within another portion of each burst period;recording physiological parameter values, including: recording firstpopulation data, the first population data including evoked response(ER) values corresponding to the evoked physiological responses to theburst of stimulation pulses for the plurality of burst periods; andrecording second population data, the second population data includingreference values that include no effect (NE) values corresponding totimes without an evoked physiological response; calculating evokedresponse metrics (ERMs) using the first and second population data, eachof the ERMs being dependent on background autonomic activity; analyzingthe ERMs to provide ERM analysis; and providing an indication ofautonomic health using the ERM analysis.
 2. The method of claim 1,wherein analyzing the ERMs includes comparing the ERMs to at least onereference value to provide the ERM analysis used to provide theindication of autonomic health.
 3. The method of claim 1, whereinanalyzing the ERMs includes trending the ERMs to provide the ERManalysis used to provide the indication of autonomic health.
 4. Themethod of claim 1, wherein the ER values include: stimulation effect(SE) values corresponding to direct responses to delivered stimulationpulses; or reflex effect (RE) values corresponding to reflex responsesafter delivered stimulation pulses; or both SE values and RE values. 5.The method of claim 1, wherein delivering the ANS dose includesdelivering bursts of neural stimulation pulses, the NE values includingvalues during times between successive bursts of neural stimulationpulses.
 6. The method of claim 1, wherein the physiological parametervalues include at least one of: heart rate values or heart ratevariability values.
 7. The method of claim 1, wherein the physiologicalparameter values include at least one of: respiratory values orrespiratory variability values.
 8. The method of claim 1, wherein thephysiological parameter values include at least one of: blood pressurevalues or blood pressure variability values.
 9. The method of claim 1,wherein recording physiological parameter values includes recordingelectrocardiograms (ECGs), and calculating ERMs includes calculatingERMs using a statistical analysis of at least one feature of the ECGs.10. The method of claim 1, wherein calculating ERMs includes: Z-scoringgroups of recorded physiological parameter values to obtain Z-scores foreach of the groups; or T-scoring groups of recorded physiologicalparameter values to obtain T-scores for each of the groups.
 11. Themethod of claim 1, wherein delivering the ANS dose includes deliveringneural stimulation to a vagus nerve.
 12. The method of claim 1, whereindelivering the ANS dose includes delivering neural stimulation to acarotid sinus nerve or a glossopharyngeal nerve.
 13. The method of claim1, wherein delivering the ANS dose includes delivering neuralstimulation to a baroreceptor region or to a chemoreceptor region.
 14. Amethod, comprising: delivering a vagal nerve stimulation (VNS) dose overa plurality of burst periods, the VNS dose including a plurality ofstimulation bursts, each stimulation burst including a plurality ofneural stimulation pulses within a portion of each burst period andanother portion of each period does not include neural stimulationpulses; sensing heart rate and recording heart rate values, including:recording first population data, the first population data includingevoked response (ER) values corresponding to the evoked heart rateeffects to stimulation bursts for the plurality of burst periods; andrecording second population data, the second population data includingreference values that include no effect (NE) values corresponding toheart rate values that are not evoked heart rate responses tostimulation bursts; calculating evoked response metrics (ERMs) toquantify a relationship between the first population data and the secondpopulation data, each of the ERMs being dependent on backgroundsympathetic activity; analyzing the ERMs to provide ERM analysis; andproviding an indication of autonomic health using the ERM analysis. 15.The method of claim 14, further comprising adjusting the ANS dose insteps, calculating an ERM for each step and comparing the ERM to areference value to monitor autonomic health.
 16. The method of claim 14,wherein analyzing the ERMs includes comparing the ERMs to at least onereference value to provide the ERM analysis used to provide theindication of autonomic health.
 17. The method of claim 14, whereinanalyzing the ERMs includes trending the ERMs to provide the ERManalysis used to provide the indication of autonomic health.
 18. Themethod of claim 14, further comprising detecting a patient status or apatient condition, and tagging the ERMs with the detected patient statusor condition.
 19. The method of claim 14, wherein: the ER values in thefirst population data include stimulation effect (SE) valuescorresponding to direct responses to stimulation bursts; and calculatingERMs includes analyzing for a SE signature.
 20. The method of claim 14,wherein: the ER values in the first population data include reflexeffect (RE) values corresponding to reflex responses after stimulationbursts; and calculating the ERM to quantify the relationship between thefirst population data and the second population data includes analyzingfor a RE signature.